Benzene-fused heterocycle derivatives and drugs containing the same as the active ingredient

ABSTRACT

A benzene-fused heteroring derivative of formula (I)  
                 
 
     , wherein all symbols are the same as described in the specification, and a non-toxic salt thereof.  
     The compound of formula (I) has an inhibitory activity against cysteine protease and therefore it is useful as an agent for the prophylaxis and/or treatment of immune diseases (autoimmune diseases, infectious diseases, etc.), inflammatory diseases (inflammatory bowel diseases, multiple cerebrosclerosis, arthritis, etc.), nerve degeneration diseases (Alzheimer&#39;s disease, muscular dystrophy, etc.), bone resorption diseases (osteoporosis, etc.), respiratory system diseases, diabetes, shock, etc.

TECHNICAL FIELD

[0001] The present invention relates to a benzene-fused heteroringderivative.

[0002] Particularly, the present invention relates to;

[0003] 1) a benzene-fused heteroring derivative of formula (I)

[0004]  wherein all symbols have the same meanings as hereinafter, and anon-toxic salt thereof,

[0005] 2) a method for the preparation thereof and

[0006] 3) a pharmaceutical agent comprising the benzene-fused heteroringderivative and non-toxic salt thereof as active ingredient.

BACKGROUND OF THE INVENTION

[0007] Cysteine protease is a generic name of proteases which have acysteine residue in the activity center and catalyze protein degradationthereat. In animal cells, a large number of cysteine proteases areknown; for example, cathepsin family, calpain family, caspase-1, etc.Cysteine protease exists in various kinds of cells extensively and playsa basic and essential role in the homeostasis, such as conversion(processing) of precursor protein into its active form and degradationof proteins which have become out of use, etc. Until now, itsphysiological effects are being vigorously studied, and as the studiesprogress and characteristics of the enzymes are revealed, cysteineprotease came to be taken as a cause of really various kinds ofdiseases.

[0008] It is revealed that cathepsin S (See J. Immunol., 161, 2731(1998)) and cathepsin L (See J. Exp. Med., 183, 1331 (1996)) play a rolein processing of major histocompatibility antigen class-II in antigenpresenting cells which play an important role in the early stage ofimmune responses. In an experimental inflammatory response model inducedby antigens, a specific inhibitor of cathepsin S showed an inhibitoryeffect (see J. Clin. Invest., 101, 2351 (1998)). It is also reportedthat in a leishmania-infected immune response model cathepsin Binhibitor inhibited an immune response and by means of this effect itinhibited the proliferation of protozoans (See J. Immunol., 161, 2120(1998)). In vitro, a result is given that a calpain inhibitor and acysteine protease inhibitor E-64 inhibited apoptosis which is induced bystimuli on T cell receptors (see J. Exp. Med., 178, 1693 (1993)).Therefore, it is conceivable that cysteine protease is much concernedwith the progress of immune responses.

[0009] It is speculated that caspase-1 or a cysteine protease similarthereto occupies an important position in the mechanism of cell deathincluding apoptosis. Therefore it is expected for a cysteine proteaseinhibitor to be used as an agent for the prophylaxis and/or treatment ofthose diseases concerning apoptosis, such as infectious diseases,deterioration or sthenia of immune function and brain function, tumors,etc. Diseases concerning apoptosis are, acquired immune deficiencysyndrome (AIDS), AIDS-related complex (ARC), adult T cell leukemia,hairy cell leukemia, spondylopathy, respiratory apparatus disorder,arthitis, HIV or HTLV-1 related diseases such as uveitis, virus-relateddiseases such as hepatitis C, cancer, collagenosis (systemic lupuserythematosus, rheumatoid arthritis, etc.), autoimmune diseases(ulcerative colitis, Sjogren's syndrome, primary biliary cirrhosis,spontaneous thrombocytopenicpurpura, autoimmune hemolytic anemia,myasthenia gravis, insulin dependent (type I) diabetes, etc.), diseasesaccompanied by thrombocytopenia (osteomyelodysplasia syndrome, periodicthrombocytopenia, aplastic anemia, spontaneous thrombocytopenia,disseminated intravascular coagulation (DIC), etc.), hepatic diseasessuch as viral hepatitis (type C, A, B, F, etc.) or hepatitismedicamentosus and cirrhosis, dementia (Alzheimer's diseases,Alzheimer's senile dementia, etc.), cerebrovascular injury, nervedegeneration diseases, adult acute respiratory distress syndrome,infectious diseases, prostatomegaly, hysteromyoma, bronchial asthma,arteriosclerosis, all kinds of lusus naturae, nephropathy, senilecataract, chronic fatigue syndrome, myodystrophy, peripheral neuropathy,etc.

[0010] Moreover, caspase-1 is concerned with various inflammatorydiseases and those diseases caused by immune disorders, by means ofinterleukin-1β (IL-1β) production. A lot of diseases are shown to beinvolved with caspase-1 including inflammatory diseases and autoimmunediseases listed below; inflammatory bowel diseases such as ulcerativecolitis, insulin-dependent (type-I) diabetes, autoimmune thyroiddiseases, infectious diseases, rejection of an organ transplantation,graft versus host diseases, psoriasis, periodontitis (above, see N. Eng.J. Med., 328, 106 (1993)), pancreatitis (see J. Interferon CytokineRes., 17, 113 (1997)), hepatitis (see J. Leuko. Biol., 58, 90 (1995)),glomerulonephritis (see Kidney Int., 47, 1303 (1995)), endocarditis (seeInfect. Immun., 64, 1638 (1996)), myocarditis (see Br. Heart J., 72, 561(1995)), systemic lupus erythematosus (see Br. J. Rheumatol., 34, 107(1995)), Hashimoto's diseases (see Autoimmunity, 16, 141 (1993)), etc.),etc. Experimentally, it is reported that in liver injury model inducedby lipopolysaccharide and D-galactosamine, a caspase-1 inhibitordepressed the symptoms, and it is expected that a caspase inhibitorshows an effect in sepsis, ischemic reperfusion and hepatitis gravis(see Am. J. Respir. Crit. Care Med., 159, 1308 (1999)).

[0011] It is also shown that cysteine protease is concerned withrheumatoid arthritis. IL-1β is shown to be concerned with this disease(see Arthritis Rheum., 39, 1092 (1996)), and in addition, asautoantibody toward calpastatin (endogenous calpain inhibitor) was foundin the serum of the patients, it is considered that increase of calpainactivity leads to the cause of diseases.

[0012] It is also known that cysteine protease causes a disease symptomby decomposing various proteins which compose the organism.

[0013] It is reported that cathepsin B plays a role in decomposingmuscular protein in the chronic phase of sepsis (see J. Clin. Invest.,97, 1610 (1996)), and in decomposing muscular protein in myodystrophymodel (see Biochem. J., 288, 643 (1992)). And it is also reported thatcalpain decomposes the myocyte cells protein of myodystrophy patients(see J. Biol. Chem., 270, 10909 (1995)).

[0014] In the ischemic reperfusion model, a result is given that calpaincauses degeneration of brain tissues by means of degradation of proteinkinase C-β (see J. Neurochem., 72, 2556 (1999)) and that a cathepsin Binhibitor inhibits nerve injury (see Eur. J. Neurosci., 10, 1723(1998)).

[0015] In the brain ischemic model, it is known that the degradation ofspectrin by calpain causes a damage and function disorder in theneurocyte (see Brain Res., 790, 1(1998)) and it is reported that anIL-1β receptor antagonist relieved the symptoms (see Brain Res. Bull.,29, 243 (1992)).

[0016] In myocardial ischemic model it is confirmed that cathepsin Bactivity increases in the lesion (see Biochem. Med. Metab. Biol., 45, 6(1991)).

[0017] In the experiment utilizing ischemic liver injury model, itproved that necrosis and apoptosis of hepacyte were induced by means ofprotein-decomposing activity of calpain (see Gastroenterology, 116, 168(1999)).

[0018] Besides, it is known that calpain causes cornea turbid incataract by means of degradation of crystalline (see Biol. Chem., 268,137 (1993)) and that in the lesion of contracted gut mucosa model it wasconfirmed that the activity of cathepsin B, H and L increased (see JPEN.J. Parenter. Enteral. Nutr., 19, 187 (1995)) and it is shown thatcysteine protease is a cause of the diseases resulting from such proteindegradation.

[0019] It has been revealed that cysteine protease is concerned withsystemic disorders of organs and tissues by shock.

[0020] It is shown that IL-1β is concerned with septic shock andsystemic inflammatory response syndrome (see Igakuno Ayumi, 169, 850(1994)) and besides, it is reported that in endotoxin shock modelinduced by lipopolysaccharide, a calpain inhibitor prevented circulatorysystem disorder, disorders of liver and pancreas and acidosis by meansof inhibitory effect of activation of nuclear factor KB (see Br. J.Pharmacol., 121, 695 (1997)).

[0021] Since it is reported that calpain is concerned with plateletcoagulation process and a calpain inhibitor prevented the coagulation ofplatelets (see Am. J. Physiol., 259, C862 (1990)), it is conceivablethat a cysteine protease inhibitor is useful for the disorder by bloodcoagulation. From the fact that calpain activity increased in the serumof the patients of purpura (thrombocytopenia) resulting from marrowtransplantation, it is conceivable that calpain is concerned with theactual disease symptoms (see Bone Marrow Transplant., 24, 641 (1999)).Caspase-1 inhibitor inhibited the apoptosis of blood vessel endothelialcells, which is seen in the early phase of purpura (thrombocytopenia)and is thought to be important for the progression of the pathologyafterwards (see Am. J. Hematol., 59, 279 (1998)), so it is expected thata cysteine protease inhibitor makes effect on purpura and hemolyticuremic syndrome.

[0022] The effect of cysteine protease and its inhibitor is beinginvestigated in the field of cancer and metastasis of cancer.

[0023] Since the proliferations of pancreas cancer cells (see CancerRes., 59, 4551 (1999)) and acute myeloid leukemia cells (see Clin. Lab.Haematol., 21, 173 (1999)) were inhibited by an inhibitor or receptorantagonist of caspase-1, it is expected that caspase-1 activity isessential for the process of proliferation of tumor cells, and that aninhibitor thereof is effective for these cancers. Cathepsin B activityincreased in colon cancer metastasis model (see Clin. Exp. Metastasis,16, 159 (1998)). Cathepsin K protein expression was recognized in humanbreast cancer cells and the relationship of cathepsin K and bonemetastasis is shown (Cancer Res., 57, 5386 (1997)). Also, a calpaininhibitor inhibited migaration of the cells and it implied thepossibility that calpain inhibition may inhibit metastasis of cancer (J.Biochem., 272, 32719 (1997)). From these, a cysteine protease inhibitoris presumed to show an inhibitory effect on the metastasis of variousmalignant tumors.

[0024] As to AIDS (see AIDS, 10, 1349 (1996)) and AIDS-related complex(ARC) (see Arch. Immunol. Ther. Exp. (Warsz), 41, 147 (1993)), it isshown that IL-1 is concerned with the progress of symptoms, so it isconceivable that cysteine protease inhibition leads to an effectivetherapy of AIDS and its complication.

[0025] Some parasites have cysteine protease activity in their body.Cysteine protease in the phagosome of malaria protozoan is an essentialenzyme for supplying nutrition of the parasites. A result is given thatthe inhibitor of cysteine protease shows an inhibitory effect of theproliferation of the protozoan (see Blood, 87, 4448 (1996)). Thus, it ispossible to apply the inhibitor of cysteine protease to malaria.

[0026] In Alzheimer-type dementia, it is said that adhesion ofnon-physiological protein called amyloid to brain is deeply involvedwith nervous function disorders. Cysteine protease has an activity ofgenerating amyloid by decomposing its precursor protein. Clinically, itis shown that cathepsin B is an enzyme that possesses a processingactivity of amyloid proteins in the brains of Alzheimer-type dementiapatients (see Biochem. Biophys. Res. Commun., 177, 377 (1991)). Also,expressions of cathepsin B protein (see Virchows Arch. A. Pathol. Anat.Histpathol., 423, 185 (1993)), cathepsin S protein (see Am. J. Pathol.,146, 848 (1995)) and calpain protein (see Proc. Natl. Acad. Sci. USA,90, 2628 (1993)) and increase of caspase-1 activity (see J. Neuropathol.Exp. Neurol., 58, 582 (1999)) were confirmed in the brain lesions.Besides, by the fact that calpain is concerned with the formation ofpaired helical filaments which accumulate in Alzheimer dementia patientsand production of protein kinase C which stabilizes the protein byphosphorylation (see J. Neurochem., 66, 1539 (1996)) and by theknowledge that caspase is concerned with neurocyte death by β amyloidprotein adhesion (see Exp. Cell Res., 234, 507 (1997)), it is impliedthat cysteine protease is concerned with the disease symptoms.

[0027] As to Huntington's chorea, cathepsin H activity increased in thepatient's brain (see J. Neurol. Sci., 131, 65 (1995)), and the ratio ofactivated form of calpain increased (see J. Neurosci., 48, 181 (1997)).In Parkinson's diseases, the increase of expression of m-calpain wasrecognized in the mesencephalon of the patients (see Neuroscience, 73,979 (1996)) and IL-1β protein was expressed in brain (see Neurosci.Let., 202, 17 (1995)). Therefore, it is speculated that cysteineprotease is concerned with the genesis and progress of these diseases.

[0028] Besides, in the central nervous system, spectrin degradation bycalpain is found in the process of injury on neurocyte observed in thetraumatic brain injury model (see J. Neuropathol. Exp. Neurol., 58, 365(1999)).

[0029] In spinal cord injured model it was recognized that in glia cellscalpain messenger RNA increased and its activity increased in the lesionand the possibility was shown that calpain had much to do with thedegeneration of myelin and actin after injury (see Brain Res., 816, 375(1999)). And IL-1β was shown to be concerned with the genesis ofmultiple sclerosis (see Immunol. Today, 14, 260 (1993)). Therefore, itis conceivable that a cysteine protease inhibitor is promising as anagent for the treatment of these nerve-injuring diseases.

[0030] Normally, cathepsin S and cathepsin K do not exist in humanarterial walls but it was confirmed that they expressed in arterialsclerosis lesion and they had an decomposing activity of alveoluselastica (see J. Clin. Invest., 102, 576 (1998)) and a calpain inhibitorand antisense of m-calpain inhibited the proliferation of human bloodvessel smooth muscle cells and it is shown that m-calpain is concernedwith the proliferation of smooth muscle (see Arteioscler. Thromb. Vssc.Biol., 18, 493 (1998)), so it is conceivable that a cysteine proteaseinhibitor is promising for the treatment of blood vessel lesion such asarteriosclerosis, restenosis after percutaneous transluminal coronaryangioplasty (PTCA), etc.

[0031] It is reported that in liver, cathepsin B is activated in theprocess of injuring hepatocyte by bile acid (see J. Clin. Invest., 103,137 (1999)) and so it is expected that a cysteine protease inhibitor iseffective for cholestatic cirrhosis.

[0032] In lungs and respiratory system, it is shown that cathepsin S isan enzyme that plays a role in elastin degradation by alveolusmacrophages (see J. Biol. Chem., 269, 11530 (1994)), so it is probablethat cysteine protease is a cause of pulmonary emphysema. And it is alsoshown that lung injury (see J. Clin. Invest., 97, 963 (1996)), lungfibrosis (see Cytokine, 5, 57 (1993)) and bronchial asthma (see J.Immunol., 149, 3078 (1992)) are caused by production of IL-1β bycaspase-1.

[0033] It is pointed out that cysteine protease is also concerned withdiseases concerning bones and cartilages. Cathepsin K is specificallyrecognized in osteoclast and it has a decomposing activity against bonematrix (see J. Biol. Chem., 271, 12517 (1996)), so its inhibitor isexpected to show an effect against osteoporosis, arthritis, rheumatoidarthritis, osteoarthritis, hypercalcemia and osteometastasis of cancer,where pathologic bone resorption is recognized. And since IL-1β is shownto be concerned with bone resorption and cartilage degradation, and acaspase-1 inhibitor and IL-1β receptor antagonist inhibit the boneresorption and symptoms of arthritis, a caspase-1 inhibitor and IL-1βreceptor antagonist are expected to be effective for arthritis (seeCytokine, 8, 377 (1996)) and osteoporosis (J. Clin. Invest., 93, 1959(1994)). And it is reported that IL-1β is also concerned withosteoarthritis (see Life Sci., 41, 1187 (1987)).

[0034] Cysteine protease is involved with production of varioushormones. Since increase of messenger RNA of cathepsin S was recognizedby stimuli of thytropin on thyroid epitheliocyte strains (see J. Biol.Chem., 267, 26038 (1992)), it is conceivable that a cysteine proteaseinhibitor is effective for hyperthyrodism.

[0035] Since quantity and activity of cathepsin B protein increased inthe gingival sulcus liquid of periodontitis patients (see J. Clin.Periodontol., 25, 34 (1998)), it is pointed out that cysteine proteaseis concerned with periodontitis.

[0036] Therefore, it is expected that the compound that possesses theinhibitory activity of cysteine protease is useful as an agent for theprophylaxis and/or treatment of inflammatory diseases (periodontitis,arthritis, inflammatory bowel diseases, infectious diseases,pancreatitis, hepatitis, glomerulonephritis, endocarditis, myocarditis,etc.), diseases induced by apoptosis (graft versus host diseases,rejection of an organ transplantation, acquired immune deficiencysyndrome (AIDS), AIDS-related complex (ARC), adult T cell leukemia,hairy cells leukemia, spondylopathy, disorders of respiratory apparatus,arthritis, HIV or HTLV-1 related diseases such as uveitis, virus-relateddiseases such as hepatitis C, cancer, collagenosis (systemic lupuserythematosus, rheumatoid arthritis, etc.), ulcerative colitis,Sjögren's syndrome, primary biliary cirrhosis, spontaneousthrombocytopenic purpura, autoimmune hemolytic anemia, myastheniagravis, autoimmune diseases such as insulin dependent (type I) diabetes,diseases accompanying thrombocytopenia (osteomyelodysplasia syndrome,periodic thrombocytopenia, aplastic anemia, spontaneousthrombocytopenia, disseminated intravascular coagulation (DIC), etc.),hepatic diseases such as viral hepatitis (type A, B, C, F, etc.) orhepatitis medicamentosus and cirrhosis, dementia such as Alzheimer'sdiseases and Alzheimer's senile dementia, cerebrovascular injury, nervedegeneration diseases, adult acute respiratory distress syndrome,infectious diseases, prostatomegaly, hysteromyoma, bronchial asthma,arteriosclerosis, all kinds of lusus naturae, nephropathy, senilecataract, chronic fatigue syndrome, myodystrophy, peripheral neuropathy,etc.), diseases induced by disorders of immune response (graft versushost diseases, rejection of an organ transplantation, allergic diseases(bronchial asthma, atopic dermatitis, allergic rhinitis, pollinosis,diseases induced by house dusts, irritable pneumonia, food allergy,etc.), psoriasis, rheumatoid arthritis, etc.), autoimmune diseases(insulin-dependent (type I) diabetes, systemic lupus erythematosus,Hashimoto's diseases, multiple sclerosis, etc.), disease by degradationvarious proteins which compose the organism (myodystrophy, cataract,periodontitis, hepatocyte disease by bile acid such as cholestaticcirrhosis, etc.), decomposition of alveolus elastica such as pulmonaryemphysema, ischemic diseases (brain ischemia, brain disorders(encephalopathy) by ischemic reperfusion, myocardial infarction,ischemic hepatopathy, etc.), shock (septic shock, systemic inflammatoryresponse syndrome, endotoxin shock, acidosis, etc.), circulatory systemdisorders (arteriosclerosis, restenosis after percutaneous transluminalcoronary angioplasty (PTCA), etc.)), blood coagulation disorders(thrombocytopenic purpura, hemolytic uremic syndrome, etc.), malignanttumor, acquired immune deficiency syndrome (AIDS) and AIDS-relatedcomplex (ARC), parasitic diseases such as malaria, nerve degenerativediseases (Alzheimer-type dementia, Huntington's chorea, Parkinson'sdiseases, multiple sclerosis, traumatic encephalopathy, traumaticspondylopathy, etc.), pulmopathy such as lung fibrosis, bone resorptiondiseases (osteoporosis, rheumatoid arthritis, arthritis, osteoarthritis,hypercalcemia, osteometastasis of cancer, etc.), endocrinesthenia suchas hyperthyroidism.

[0037] On the other hand, what is the most important for inhibitors ininhibiting the activity of proteases is, the special reaction site whichinteracts with the amino acid residue that is the activity center ofproteases. The surrounding structure of the reaction sites arerepresented by - - - P3P2P1-P1′P2′P3′ - - - , centering peptide binding(P1-P1′) of the reaction site, and at P1 site there exist amino acidresidues fitting the substance specificity of proteases which theinhibitors aim. Some reaction sites against cysteine proteases areknown, for Example, in the specification of WO99/54317, the followingsare described;

[0038] P1 position against calpain I, II (norvaline, phenylalanine,etc.),

[0039] P1 position against calpain I (arginine, lysine, tyrosine,valine, etc.),

[0040] P1 position against papain (homophenylalanine, arginine, etc.),

[0041] P1 position against cathepsin B (homophenylalanine,phenylalanine, tyrosine, etc.),

[0042] P1 position against cathepsin S (valine, norleucine,phenylalanine, etc.),

[0043] P1 position against cathepsin L (homophenylalanine, lysine,etc.),

[0044] P1 position against cathepsin K (arginine, homophenylalanine,leucine, etc.),

[0045] P1 position against caspase (aspartic acid).

[0046] On the other hand, in the specification of JP-A-6-192199, it isdisclosed that a ketone derivative of formula (A) is effective as athiol protease inhibitor,

[0047] wherein R^(1A) is hydrogen, R^(10A)—CO—, R^(10A)—OCO—,R^(10A)—SO₂— or R^(10A)—NHCO—,

[0048] (1) when AA is —S—, —SO— or —SO₂, R^(9A) is C6-C14 aryloptionally containing substituent(s) or —(CH₂)_(m) ^(A)—X^(A), whereinX^(A) is hydrogen, hydroxy, C1-C5 alkylthio, C2-C6 alkoxycarbonylamino,heterocycle residue optionally containing substituent(s), amino, C1-C5monoalkylamino, C2-C10 dialkylamino, C2-6 acylamino, halogen, C1-C5alkoxy, C6-C14 aryl optionally containing substituent(s) or C6-C14aryloxy optionally containing substituent(s), and m^(A) is an integer of0 or 1 to 15,

[0049] (2) when AA is —O—, R^(9A) is hydrogen or —(CH₂)_(IA)—X^(A),wherein I^(A) is an integer of 1 to 15,

[0050] (3) when AA is —NR^(11A)—, R^(9A) is C6-C14 aryl optionallycontaining substituent(s), —(CH₂)_(m) ^(A)—X^(A), R^(9A) and R^(11A) aretaken together to form an N-containing heteroring optionally containingsubstituent(s) (the essential parts are extracted to explainsubstituents).

[0051] And in the specification of JP-A-7-70058, it is disclosed thatα-aminoketone derivative of formula (B)

[0052] or its pharmaceutically acceptable salt shows a strong inhibitoryactivity against thiol protease, wherein R^(1B) is hydrogen,R^(4B)—O—C(O)— or R^(4B)—C(O)—, wherein R^(4B) is C1-C20 alkyloptionally containing a substituent or more selected from C3-C15cycloalkyl, C6-C14 aryl optionally containing substituent(s),heterocycle residue optionally containing substituent(s), C3-C15cycloalkyloxy, C6-C14 aryloxy optionally containing substituent(s),aralkyloxy optionally containing substituent and C6-C14 arylthiooptionally containing substituent(s); C2-C10 alkenyl optionallysubstituted with C6-C14 aryl optionally containing substituent(s);C6-C14 aryl optionally containing substituent(s) or heterocycle residueoptionally containing substituent), R^(2B) and R^(3B) are eachindependently, hydrogen or C1-C20 alkyl optionally containing asubstituent,

[0053] is heterocycle residue optionally containing a substituent, n^(B)is 0 or 1, m^(B) is an integer of 1 to 5.

DISCLOSURE OF THE INVENTION

[0054] The present inventors have energetically investigated to find outsuch compounds that have cysteine protease inhibitory activity and foundthat the benzene-fused heteroring derivative of formula (I) of thepresent invention accomplishes the purpose.

[0055] The benzene-fused heteroring of formula (I) of the presentinvention is not known at all as a cysteine protease inhibitor at all.

[0056] The present invention relates to

[0057] (1) an oxadiazole derivative of formula (I),

[0058] wherein R is

[0059] (i) hydrogen,

[0060] (ii) C1-8 alkyl,

[0061] (iii) CycA,

[0062] (iv) C1-8 alkyl substituted with a group selected from halogenatom, CycA, nitro, CF₃ and cyano,

[0063]  CycA is a C3-15 mono-, bi- or tri-cyclic carboring or a mono-,bi- or tri-cyclic 3-15 membered heteroring comprising 1-4 of nitrogen,1-2 of oxygen and/or 1 of sulfur;

[0064] R¹⁶ is

[0065] (1) C1-8 alkyl,

[0066] (2) C2-8 alkenyl,

[0067] (3) C2-8 alkynyl,

[0068] (4) CycA or

[0069] (5) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with agroup selected from halogen atom, nitro, CF₃, cyano, CycA, NR¹⁸R¹⁹ and—NHC(O)-CycA;

[0070] R¹⁷, R¹⁸ and R¹⁹ each independently represents hydrogen or C1-4alkyl,

[0071] AA¹ is

[0072] (i) a single bond, or

[0073] wherein R¹ and R² are the same or different to represent

[0074] (i) hydrogen,

[0075] (ii) C1-8 alkyl,

[0076] (iii) CycA or

[0077] (iv) C1-8 alkyl substituted with 1-5 of group selected from thefollowing (1) to (8):

[0078] (1) —NR² ¹R² ²,

[0079] (2) —O² ³,

[0080] (3) —SR² ⁴,

[0081] (4) —COR² ⁵,

[0082] (5) —NR² ⁶CONR² ¹R² ²,

[0083] (6) guanidino,

[0084] (7) CycA,

[0085] (8) —NR² ⁶SO₂R² ¹; or

[0086] R¹ and R² are taken together to form C2-8 alkylene, wherein onecarbon atom may be replaced by oxygen, sulfur or —NR²⁰— and the alkylenemay be substituted with —NR²¹R²² or —OR²³,

[0087] R²⁰ is hydrogen, C1-4 alkyl, —COO—(C1-4 alkyl), phenyl or C1-4alkyl substituted with phenyl,

[0088] R²¹, R²², R²³, R²⁴ and R²⁶ are the same or different to representhydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,

[0089] R²⁵ is C1-4 alkyl, phenyl, —NR²¹R²², wherein all symbols have thesame meaning as above, —OR²³, wherein R²³ is the same meaning as above,or C1-4 alkyl substituted with phenyl,

[0090] R³ is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted withphenyl or

[0091] R³ is taken together with R¹ to form C2-6 alkylene, wherein onecarbon atom may be replaced by oxygen, sulfur or —NR²⁰— and the alkylenemay be substituted with —NR²¹R²² or —OR²³, or when AA¹ is

[0092] AA¹ and R may be taken together to form

[0093] is a 5-12 membered mono- or bi-cyclic heteroring and the othersymbols are the same meanings as above,

[0094] AA² is

[0095] (i) a single bond,

[0096] wherein R⁴ and R⁵ are the same or different to represent

[0097] (1) hydrogen,

[0098] (2) C1-8 alkyl,

[0099] (3) CycA or

[0100] (4) C1-8 alkyl substituted with 1-5 of group selected from thefollowing (a) to (h):

[0101] (a) —NR⁴ ¹R⁴ ²,

[0102] (b) —OR⁴ ³,

[0103] (c) —SR⁴ ⁴,

[0104] (d) —COR⁴ ⁵ ,

[0105] (e) —NR⁴ ⁶CONR⁴ ¹R⁴ ²,

[0106] (f) guanidino,

[0107] (g) CycA,

[0108] (h) —NR⁴ ⁶SO₂R⁴ ¹; or

[0109] R⁴ and R⁵ are taken together to form C2-8 alkylene, wherein onecarbon atom may be replaced by oxygen, sulfur or —NR⁴⁰— and the alkylenemay be substituted with —NR⁴¹R⁴² or —OR⁴³,

[0110] R⁴⁰ is hydrogen, C1-4 alkyl, —COO—(C1-4 alkyl), phenyl or C1-4alkyl substituted with phenyl,

[0111] R⁴¹, R⁴², R⁴³, R⁴⁴ and R⁴⁶ are the same or different to representhydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,

[0112] R⁴⁵ is C1-4 alkyl, phenyl, —NR⁴¹R⁴², wherein all symbols are thesame meaning as above, —OR⁴³, wherein R⁴³ is the same meaning as above,or C1-4 alkyl substituted with phenyl,

[0113] R⁶ is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted withphenyl or

[0114] R⁶ is taken together with R⁴ to form C2-6 alkylene, wherein onecarbon atom may be replaced by oxygen, sulfur or —NR⁴⁰— and the alkylenemay be substituted with —NR⁴¹R⁴² or —OR⁴³,

[0115] R⁴⁸ is hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substitutedwith phenyl or when AA¹ is a single bond, R⁴⁸ and R may be takentogether to form C2-6 alkylene, wherein one carbon atom may be replacedby oxygen, sulfur or —NR⁴⁷, wherein R⁴⁷ is hydrogen or C1-4 alkyl,

[0116] CycC is a 3-17 membered mono- or bi-cyclic heteroring,

[0117] CycD is a C3-14 mono- or bi-cyclic carboring or a 3-14 memberedmono- or bi-cyclic heteroring, or

[0118] AA² and AA¹ are taken together to form

[0119] wherein CycE is a 4-18 membered mono- or bi-cyclic heteroring,

[0120] CycF is a 5-8 membered monocyclic heteroring, and the othersymbols have the same meanings as above,

[0121] R⁷ and R⁸ are the same or different to represent

[0122] (i) hydrogen,

[0123] (ii) C1-8 alkyl,

[0124] (iii) CycA or

[0125] (iv) C1-8 alkyl substituted with 1-5 of group selected from thefollowing (1) to (8);

[0126] (1) —NR⁶¹R⁶²,

[0127] (2) —OR⁶³,

[0128] (3) —SR⁶⁴,

[0129] (4) —COR⁶⁵,

[0130] (5) —NR⁶⁶CONR⁶¹R⁶²,

[0131] (6) guanidino,

[0132] (7) CycA,

[0133] (8) —NR⁶⁶SO₂R⁶¹, or

[0134] R⁷ and R⁸ are taken together to form C2-8 alkylene, wherein onecarbon atom may be replaced by oxygen, sulfur or —NR⁶⁰— and the alkylenemay be substituted with —NR⁶¹R⁶² or —OR⁶³,

[0135] R⁶⁰ is hydrogen, C1-4 alkyl, —COO—(C1-4 alkyl), phenyl or C1-4alkyl substituted with phenyl,

[0136] R⁶¹, R⁶², R⁶³, R⁶⁴ and R⁶⁶ are the same or different to representhydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,

[0137] R⁶⁵ is C1-4 alkyl, phenyl, —NR⁶¹R⁶², wherein all symbols are thesame meanings as above, —OR⁶³, wherein R⁶³ is the same meaning as above,or C1-4 alkyl substituted with phenyl,

[0138] R⁹ is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted withphenyl or

[0139] R⁹ is taken together with R⁷ to form C2-6 alkylene, wherein onecarbon atom may be replaced by oxygen, sulfur or —NR⁶⁰— and the alkylenemay be substituted with —NR⁶¹R⁶² or —OR⁶³,

[0140] r is an integer of 1 to 4,

[0141] in the ring of (i), (ii) and (iii), one saturated carbon atom ortwo may be replaced by

[0142] (1) oxygen,

[0143] (2) —S(O)_(s)— or

[0144] (3) —NR⁸³—,

[0145] wherein s is 0 or an integer of 1 to 2,

[0146] R⁸³ is

[0147] (a) hydrogen,

[0148] (b) C1-8 alkyl,

[0149] (c) CycA or

[0150] (d) C1-8 alkyl substituted with 1-5 of group selected from CycA,guanidino, —COR⁶⁸, —NR⁶⁹R⁷⁰, —OR⁶⁹, cyano and —P(O)(OR⁷⁵)₂,

[0151] R⁶⁸ is C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,

[0152] R⁶⁹ and R⁷⁰ are the same or different to represent hydrogen, C1-4alkyl, phenyl or C1-4 alkyl substituted with phenyl,

[0153] R⁷⁵ is hydrogen, C1-8 alkyl, phenyl or C1-4 alkyl substitutedwith 1-5 of phenyl, cyano or halogen atom and the ring of (i), (ii) and(iii) may be condensed with a C5-C8 carbon ring or a 5-8 memberedheteroring containing one nitrogen atom or two, one oxygen atom and/or asulfur atom,

[0154] q is an integer of 0 or 1 to 5,

[0155] R¹⁰ is

[0156] (i) C1-8 alkyl,

[0157] (ii) C2-8 alkenyl,

[0158] (iii) C2-8 alkynyl,

[0159] (iv) halogen atom,

[0160] (v) CycA,

[0161] (vi) —COR⁷¹,

[0162] (vii) —NR⁷²R⁷³,

[0163] (viii) —OR⁷⁴ or

[0164] (ix) C1-8 alkyl substituted with 1 to 5 of groups selected fromthe following <1> to <7>:

[0165] <1> CycA,

[0166] <2> guanidino,

[0167] <3> —COR⁷¹,

[0168] <4> —NR⁷²R⁷³,

[0169] <5> —OR⁷⁴,

[0170] <6> cyano or

[0171] <7> —P(O)(OR⁷⁸)₂,

[0172] wherein R⁸² is hydrogen, C1-8 alkyl, phenyl or C1-4 alkylsubstituted with 1 to 5 of phenyl, cyano or halogen atom,

[0173] R⁷¹ is

[0174] (1) C1-8 alkyl,

[0175] (2) CycA,

[0176] (3) —NR⁷²R⁷³,

[0177] (4) —OR⁷⁴, or

[0178] (5) C1-8 alkyl substituted with CycA;

[0179] R⁷² and R⁷³ are the same or different to represent

[0180] (1) hydrogen,

[0181] (2) C1-8 alkyl,

[0182] (3) CycA or

[0183] (4) C1-8 alkyl substituted with 1 to 5 of groups selected fromthe following (a) to (f):

[0184] (a) CycA,

[0185] (b) guanidino,

[0186] (c) —NR⁷⁷R⁷⁸, wherein R⁷⁷ and R⁷⁸ have the same or different torepresent hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted withphenyl,

[0187] (d) —OR⁷⁷, wherein R⁷⁷ has the same meaning as above,

[0188] (e) —COR⁷⁶, wherein R⁷⁶ has C1-4 alkyl, phenyl, —NR⁷⁷R⁷⁸, whereinall symbols have the same meanings as above, —OR⁷⁷, wherein R⁷⁷ has thesame meaning as above, or C1-4 alkyl substituted with phenyl, and

[0189] (f) cyano;

[0190] R⁷⁴ is

[0191] (1) hydrogen,

[0192] (2) C1-8 alkyl,

[0193] (3) CycA, or

[0194] (4) C1-8 alkyl substituted with 1 to 5 of groups selected fromthe following (a) to (h), wherein one carbon atom may be replaced byoxygen, sulfur atom or —NR⁸⁴:

[0195] (a) CycA,

[0196] (b) guanidino,

[0197] (c) —SiR⁷⁹R⁸⁰R⁸¹, wherein R⁷⁹, R⁸⁰ and R⁸¹ are the same ordifferent to represent C1-8 alkyl, phenyl or C1-8 alkyl substituted withphenyl,

[0198] (d) —NR⁷⁷R⁷⁸, wherein all symbols have the same meanings asabove,

[0199] (e) —OR⁷⁷, wherein R⁷⁷ has the same meaning as above,

[0200] (f) —COR⁷⁶, wherein R⁷⁶ has the same meaning as above,

[0201] (g) cyano,

[0202] (h) —P(O)(OR⁸²)₂, wherein all symbols have the same meaning asabove;

[0203] CycA included in R, R¹, R², R⁴, R⁵, R⁷, R⁸, R¹⁰, R¹⁶, R⁷¹, R⁷²,R⁷³, R⁷⁴ and R⁸³ are the same or different and CycA, CycB, CycC, CycD,CycE and CycF, independently, may be substituted with 1 to 5 of R²⁷;

[0204] R²⁷ is

[0205] (1) C1-8 alkyl,

[0206] (2) halogen atom,

[0207] (3) —NR¹¹R¹²,

[0208] (4) —OR¹³,

[0209] (5) a C5-10 mono-or bi-cyclic carboring,

[0210] (6) nitro,

[0211] (7) CF₃,

[0212] (8) cyano,

[0213] (9) a 5-10 membered mono- or bi-cyclic heteroring

[0214] (10) —SR¹⁴,

[0215] (11) —COR¹⁵,

[0216] (12) oxo,

[0217] (13) —SO₂R¹⁵,

[0218] (14) —OCF₃ or

[0219] (15) C1-8 alkyl substituted with 1-5 of group selected from thefollowing (a) to (m)

[0220] (a) halogen atom,

[0221] (b) —NR¹¹R¹²,

[0222] (c) —OR¹³,

[0223] (d) a C5-10 mono- or bi-cyclic carboring,

[0224] (e) nitro,

[0225] (f) CF₃,

[0226] (g) cyano,

[0227] (h) a 5-10 membered mono- or bi-cyclic heteroring,

[0228] (j) —SR¹⁴,

[0229] (k) —COR¹⁵,

[0230] (l) —SO₂R¹⁵,

[0231] (m) —OCF₃,

[0232] wherein R¹¹ and R¹² are the same or different to representhydrogen, C1-4 alkyl, —COO—(C1-4 alkyl), phenyl or C1-4 alkylsubstituted with phenyl,

[0233] R¹³ and R¹⁴ are the same or different to represent hydrogen, C1-4alkyl, phenyl or C1-4 alkyl substituted with phenyl,

[0234] R¹⁵ is C1-4 alkyl, phenyl, —NR¹¹R¹², wherein all symbols have thesame meanings as above, —OR¹³, wherein R¹³ is the same meaning as above,or C1-4 alkyl substituted with phenyl, or a non-toxic salt thereof,

[0235] (2) a method for the preparation thereof and

[0236] (3) a pharmaceutical agent comprising the benzene-fusedheteroring derivative and non-toxic salt thereof as active ingredient.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0237] In the compound of formula (I), in

[0238] which AA¹ and R together form,

[0239] is a 5-12 membered heteroring containing 1-3 of nitrogen, 1 ofoxygen, and/or 1 of sulfur (this heteroring may be substituted with 1-5of R²⁷).

[0240] And to describe

[0241] concretely, it is

[0242] wherein

[0243] J¹ is oxygen, sulfur, —NR²⁹—, wherein R²⁹ is hydrogen, C1-4alkyl, CycA or C1-4 alkyl substituted with CycA, C1-3 alkylene or C2-3alkenylene,

[0244] J² is a single bond or C1-2 alkylene,

[0245] Y² is —N═CH—, —CH═N— or C1-2 alkylene,

[0246] J³ is carbonyl or C1-3 alkylene,

[0247] Y³ is C1-3 alkylene, oxygen or —NR²⁹—, wherein R²⁹ is the samemeaning as above,

[0248] R²⁸ is hydrogen, C1-4 alkyl, CycA or C1-4 alkyl substituted withCycA, or

[0249] R²⁸ is taken together with R¹to form C2-4 alkylene, and the othersymbols have the same meaning as above and each ring may be substitutedwith 1-5 of R²⁷.

[0250] In the compound of formula (I), in

[0251] which AA² represents, CycC is a 3-17 membered heteroring whichcontains 1-2 of nitrogen, 1 of oxygen and/or 1 of sulfur (this ring maybe substituted with 1-5 of R²⁷).

[0252] And to describe

[0253] concretely,

[0254] wherein

[0255] J⁴, Y⁴ and L⁴ are the same or different to represent a singlebondor C1-3 alkylene, wherein J⁴, Y⁴ and L⁴ do not represent a single bondat the same time,

[0256] J⁵ is C1-6 alkylene,

[0257] Y⁵ is a single bond, C1-3 alkylene or —NR⁶⁷—, wherein R⁶⁷ ishydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl,

[0258] J⁸ is C1-5 alkylene, wherein one carbon atom may be replaced byoxygen,

[0259] Y⁸ is a single bond or C1-4 alkylene,

[0260] L⁸ is —N— or —CH—,

[0261] and the other symbols have the same meaning as above and eachring may be substituted with 1-5 of R²⁷.

[0262] And in

[0263] which AA² represents, CycD is a C3-14 mono- or bi-cycliccarboring or 3-14 membered heteroring which contains 1-2 of nitrogen, 1of oxygen and/or 1 of sulfur (this carboring and heteroring may besubstituted with 1-5 of R²⁷).

[0264] And to describe

[0265] concretely, it is

[0266] wherein

[0267] J⁶ and Y⁶ are the same or different to represent a single bond orC1-3 alkylene, wherein J⁶ and Y⁶ do not represent a single bond at thesame time,

[0268] J⁷ is C1-6 alkylene, wherein one carbon atom may be replaced byoxygen, sulfur or —NR⁶⁷—, wherein R⁶⁷ has the same meaning as above,

[0269] J⁹ is C1-3 alkylene, oxygen, sulfur or —NR⁶⁷—, wherein R⁶⁷ is thesame meaning as above,

[0270] and the other symbols have the same meanings as above and eachring may be replaced by 1-5 of R²⁷.

[0271] In the compounds of the formula (I), in

[0272] which AA¹ and AA² together form,

[0273] CycE is a 4-18 membered heteroring which contains 1-2 ofnitrogen, 1 of oxygen and/or 1 of —S(O)_(p)— (this heteroring may besubstituted with 1-5 of R²⁷).

[0274] And to describe

[0275] concretely, it is

[0276] wherein

[0277] is a single bond or a double-bond,

[0278] J¹⁰ and Y¹⁰ are the same or different to represent a single bondor C1-3 alkylene,

[0279] L¹⁰ is a single bond, C1-3 alkylene, —NR⁵⁷—, wherein R⁵⁷ ishydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl, —N═,oxygen or —S(O)_(p)—, wherein p is 0 or an integer of 1 to 2,

[0280] J¹² and Y¹² are the same or different to represent a single bondor C1-3 alkylene,

[0281] L¹² is C1-3 alkylene, —NR⁵⁷—, wherein R⁵⁷ is the same meaning asabove), —N═, ═N—, oxygen or —S(O)_(p)—, wherein p has the same meaningas above,

[0282] and the other symbols have the same meanings as above and eachring may be substituted with 1-5 of R²⁷.

[0283] And in

[0284] which AA¹ and AA² together form,

[0285] CycF is a 5-8 membered heteroring containing 2 of nitrogen.

[0286] And to describe

[0287] concretely, it is

[0288] wherein J¹¹ is carbonyl or C2-4 alkylene and the other symbolshave the same meaning as above and the ring therein may be substitutedwith 1-5 of R²⁷.

[0289] In the present specification, C1-4 alkyl is methyl, ethyl,propyl, butyl and isomers thereof.

[0290] In the present specification, C1-8 alkyl is methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof.

[0291] In the present specification, C2-8 alkenyl is, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl containing 1-3 of double bond andisomers thereof. For example, vinyl, propenyl, butenyl, hexenyl,hexadienyl, octadienyl, etc. are included.

[0292] In the present specification, C2-8 alkynyl is ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl containing 1-3 of triple bond andisomers thereof. For example, ethynyl, propynyl, butynyl, pentynyl,hexynyl, heptynyl, octynyl, etc. are included.

[0293] In the present specification, C1-4 alkyl substituted with phenylis phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl and isomersthereof.

[0294] In the present specification, C1-8 alkyl substituted with phenylis phenylmethyl, phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl,phenylhexyl, phenylheptyl, phenyloctyl and isomers thereof.

[0295] In the present specification, C1-2 alkylene is, methylene,ethylene and isomers thereof.

[0296] In the present specification, C1-3 alkylene is, methylene,ethylene, trimethylene and isomers thereof.

[0297] In the present specification, C1-4 alkylene is methylene,ethylene, trimethylene, tetramethylene and isomers thereof.

[0298] In the present specification, C1-5 alkylene is methylene,ethylene, trimethylene, tetramethylene, pentamethylene and isomersthereof

[0299] In the present specification, C1-6 alkylene is methylene,ethylene, trimethylene, tetramethylene, pentamethylene, hexamethyleneand isomers thereof.

[0300] In the present specification, C2-4 alkylene is ethylene,trimethylene, tetramethylene and isomers thereof.

[0301] In the present specification, C2-6 alkylene is ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene and isomersthereof.

[0302] In the present specification, C2-8 alkylene is ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene, octamethylene and isomers thereof.

[0303] In the present specification, C2-6 alkylene whose one carbon atommay be replaced by oxygen, sulfur, —NR²⁰—, —NR⁴⁰— or —NR⁶⁰— is ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene and isomersthereof, wherein one carbon atom thereof may be replaced by oxygen,sulfur, —NR²⁰—, —NR⁴⁰—, or —NR⁶⁰—, for example, such groups are—CH₂—O—CH₂—, —CH₂—CH₂—O—CH₂—, —CH₂—CH₂—S—CH₂—, —CH₂—CH₂—NH—CH₂—,—CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—S—CH₂—CH₂—, —CH₂—CH₂—NH—CH₂—CH₂—,—CH₂—CH₂—N(CH₃)—CH₂—CH₂—, etc.

[0304] In the present specification, C2-8 alkylene whose one carbon atommay be replaced by oxygen, sulfur, —NR²⁰—, —NR⁴⁰— or —NR⁶⁰— is ethylene,trimethylene, tetramethylene, pentamethylene, hexamethylene,heptamethylene, octamethylene and isomers thereof, wherein one carbonatom may be replaced by oxygen, sulfur, —NR²⁰—, —NR⁴⁰— or —NR⁶⁰—, forexample, such groups are —CH₂—O—CH₂—, —CH₂—CH₂—O—CH₂—, —CH₂—CH₂—S—CH₂—,—CH₂—CH₂—NH—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH₂—S—CH₂—CH₂—,—CH₂—CH₂—NH—CH₂—CH₂—, —CH₂—CH₂—N(CH₃) —CH₂—CH₂—, etc.

[0305] In the present specification, C2-3 alkenylene means vinylene andallylene and isomers thereof.

[0306] In the present specification, C1-4 alkoxy is methoxy, ethoxy,propoxy, butoxy and isomers thereof.

[0307] In the present specification, C3-6 alkylene is trimethylene,tetramethylene, pentamethylene, hexamethylene and isomers thereof.

[0308] In the present specification, halogen atom means chlorine,fluorine, bromine and iodine atom.

[0309] In the present specification, mono- or bi-cyclic C5-10 carboringis mono- or bi-cyclic C5-10 carboaryl or partially or completelysaturated one thereof. For example, cyclopentane, cyclohexane,cycloheptane, cyclopentene, cyclohexene, cyclopentadiene,cyclohexadiene, benzene, pentalene, indene, naphthalene, azulene,perhydropentalene, perhydroindene, perhydronaphthalene, perhydroazulene,adamantyl ring, etc. are included.

[0310] In the present specification, mono-, bi- or tri-cyclic C3-15carboring is mono-, bi- or tri-cyclic carboaryl or partially orcompletely saturated one thereof. For example, cyclopropane,cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene,cyclohexene, cyclopentadiene, cyclohexadiene, benzene, pentalene,indene, naphthalene, azulene, fluorene, phenanthrene, anthracene,acenaphthylene, biphenylene, perhydropentalene, perhydroindene,perhydronaphthalene, perhydroazulene, perhydrofluorene,perhydrophenanthrene, perhydroanthracene, perhydroacenaphthylene,perhydrobiphenylene, adamantyl ring etc. are included.

[0311] In the present specification, mono- or bi-cyclic 5-10 memberedheteroring containing 1-4 of nitrogen, 1 of oxygen and/or sulfur ismono- or bi-cyclic 5-10 membered heteroaryl containing 1-4 of nitrogen,1 of oxygen and/or sulfur or partially or completely saturated onethereof.

[0312] Above 5-10 membered mono- or bi-cyclic heteroaryl containing 1-4of nitrogen, 1 of oxygen and/or 1 of sulfur is, for example, pyrrole,imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyrane, oxepine,thiophene, thiaine (thiopyrane), thiepine, oxazole, isooxazole,thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,benzoxazole, benzothiazole, benzoimidazole, etc.

[0313] Above partially or completely saturated mono- or bi-cyclic 5-10membered heteroaryl containing 1-4 of nitrogen, 1 of oxygen and/or 1 ofsulfur is, for example, pyrroline, pyrrolidine, imidazoline,imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine,pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyridine,tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran,tetrahydrofuran, dihydropyrane, tetrahydropyrane, dihydrothiophene,tetrahydrothiophene, dihydrothiaine (dihydrothiopyrane),tetrahydrothiaine (tetrahydrothiopyrane), oxazoline (dihydrooxazole),oxazolidine (tetrahydroxazole), dihydroisoxazole, tetrahydroisoxazole,oxadiazoline (dihydroxadiazole), oxadiazolidine (tetrahydroxadiazole),thiazoline (dihydrothiazole), thiazolidine (tetrahydrothiazole),dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine,indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran,dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline,dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzoimidazole,etc.

[0314] In the present specification, a 3-15 membered mono-, bi- ortri-cyclic heteroring containing 1-4 of nitrogen, 1-2 of oxygen and/or 1of sulfur is 3-15 membered mono-, bi- or tri-cyclic heteroarylcontaining 1-4 of nitrogen, 1-2 of oxygen and/or 1 of sulfur orpartially or completely saturated one thereof.

[0315] Above 3-15 membered mono-, bi- or tri-cyclic heteroringcontaining 1-4 of nitrogen, 1-2 of oxygen and/or 1 of sulfur is, forexample, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine,pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyrane,oxepine, oxazepine, thiophene, thiaine (thiopyrane), thiepine, oxazole,isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine,oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,benzoxazole, benzoxadiazole, benzothiazole, benzoimidazole, carbazole,acridine ring, etc.

[0316] Above partially or completely saturated mono-, bi- or tri-cyclic5-15 membered heteroring containing 1-4 of nitrogen, 1-2 of oxygenand/or 1 of sulfur is, aziridine, oxirane, azetidine, oxetane, thiirane,thietane, pyrroline, pyrrolidine, imidazoline, imidazolidine,triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline,pyrazolidine, piperidine, piperazine, tetrahydropyridine,tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran,tetrahydrofuran, dihydropyrane, tetrahydropyrane, dihydrothiophene,tetrahydrothiophene, dihydrothiaine (dihydrothiopyrane),tetrahydrothiaine (tetrahydrothiopyrane), oxazoline (dihydroxazole),oxazolidine (tetrahydroxazole), dihydroisoxazole, tetrahydroisoxazole,oxadiazoline (dihydroxadiazole), oxadiazolidine (tetrahydroxadiazole),thiazoline (dihydrothiazole), thiazolidine (tetrahydrothiazole),dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine,indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran,dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, perhydroindazole,dihydroquinoline, tetrahydroquinoline, perhydroquinoline,dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline,dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine,dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine,dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline,dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline,dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline,dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole,perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzoimidazole,benzoxazepine, benzoxadiazepine, benzothiazepine, benzothiadiazepine,benzazepine, benzodiazepine, indoloxazepine, indolotetrahydroxazepine,indoloxadiazepine, indolotetrahydroxadiazepine, indolothiazepine,indolotetrahydrothiazepine, indolothiadiazepine,indolotetrahydrothiadiazepine, indolazepine, indolotetrahydroazepine,indolodiazepine, indolotetrahydrodiazepine, benzofurazane,benzothiadiazole, benzotriazole, camphor, imidazothiazole,dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole,dihydroacridine, tetrahydroacridine, perhydroacridine, dioxolane,dioxane, dioxazine ring etc.

[0317] In the present specification, C5-8 carboring is C5-8 mono-cycliccarboaryl or partially or completely saturated one thereof. For example,cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopentene,cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene,cycloheptadiene, cyclooctadiene, benzene, cycloheptatriene,cyclooctatriene, etc. are included.

[0318] In the present specification, 5-8 membered heteroring containing1 or 2 of nitrogen, 1 of oxygen and/or 1 of sulfur is, mono-cyclic 5-8membered heteroaryl containing 1 or 2 of nitrogen, 1 of oxygen and/or 1of sulfur, or partially or completely saturated one thereof. Forexample, pyridine, piperidine, pyrrole, pyrrolidine, azepine,hexahydroazepine, diazepine, furan, dioxane, dioxole, pyran, oxepine,oxocine, thiophene, thiane, thiepine, oxathiolane, oxazolidine,pyrazole, oxazole, pyrazine, pyrimidine, pyridazine, etc. are included.

[0319] In the present specification, a 5-12 membered heteroringcontaining 1-3 of nitrogen, 1 of oxygen and/or 1 of sulfur atom, i.e.

[0320] is, for example, a ring represented by

[0321] Specifically, 2-oxo-1,3,4-triazoline, 5-oxo-1,2,4-oxadiazoline,5-oxo-1,2,4-thiadiazoline, 4-oxoimidazoline,3,4-dihydro-4-oxopyrimidine, 3,4,5,6-tetrahydro-4-oxopyrimidine,2-oxoindoline, 2-oxo-tetrahydroquinoline, 1,2-dihydro-2-oxoquinazoline,1,2-dihydro-2-oxoquinoxaline, 3-oxopyrazolidine,perhydro-3-oxopyridazine, 2-oxo-1,3,4-oxadiazolidine,perhydro-2-oxo-1,3,4-oxadiazine, etc. are included.

[0322] In the specification, 3-17 membered heteroring containing 1-2 ofnitrogen, 1 of oxygen and/or 1 of sulfur represented by CycC is, forexample, a ring represented by

[0323] Specifically, pyrrolidine, imidazolidine, pyrazolidine,piperidine, piperazine, perhydropyrimidine, perhydropyridazine,thiazolidine, indoline, isoindoline, tetrahydroquinoline,tetrahydroisoquinoline, etc. are included.

[0324] In the specification, a C3-14 mono- or bi-cyclic carboring or3-14 membered heteroring containing 1-2 of nitrogen, 1 of oxygen, and/or1 of sulfur represented by CycD is, for example, a ring represented by

[0325] Specifically, cyclopentane, cyclohexane, cycloheptane, benzene,indan, tetrahydronaphthalene, oxorane, oxane, thiorane, thian,pyrrolidine, piperidine, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,7-azabicyclo[2.2.1]heptane, 7-oxobicyclo[2.2.1]heptane,7-thiabicyclo[2.2.1]heptane, etc. are included.

[0326] In the specification, 4-18 membered heteroring containing 1-2 ofnitrogen, 1 of oxygen and/or 1 of —S(O)_(p)—, i.e. CycE is, for example,a ring represented by

[0327] Specifically, 2-oxopyrrolidine, 2-oxopiperidine,2-oxoperhydroazepine, 2-oxopiperazine, 3-oxomorpholine,1,1,-dioxo-3-isothiazolidine, 1,1-dioxo-3-isothiazine, 4-oxodiazepine,2-oxoindoline, 2-oxo-tetrahydroquinoline,1,1-dioxo-3-benzisothiazolidine, 1,1-dioxo-3-benzisothiazine, etc. areincluded.

[0328] In the present invention, 5-8 membered heteroring which contains2 of nitrogen. i.e. CycF is, for example, a ring represented by

[0329] Specifically, 2,4-dioxoimidazolidine, 2-oxopiperazine,2-oxoperhydrodiazepine substituted by R¹ and R² are included.

[0330] In the present invention, as may be easily understood by thoseskilled in the art, the symbol:

[0331] indicates that the substituent attached thereto is in front ofthe sheet (β-position) unless specified,

[0332] indicates that the substituent attached thereto is behind thesheet (α-position) unless specified, and

[0333] indicates that the substituent attached thereto is in β-positionor α-position or a mixture thereof.

[0334] In the formula (I), all groups represented by R are preferable,but preferably, R is

[0335] (i) hydrogen,

[0336] (ii) C1-8 alkyl,

[0337] (iii) CycA,

[0338] (iv) C1-8 alkyl substituted with a group selected from CycA andnitro,

[0339] more preferably, C1-8 alkyl or C1-8 alkyl substituted with CycAor nitro, or

[0340] Any group represented by R¹⁶ is preferable, but more preferably,R¹⁶ is

[0341] [I] (1) C1-8 alkyl,

[0342] (2) C2-8 alkenyl,

[0343] (3) C2-8 alkynyl,

[0344] (4) CycA, or

[0345] (5) C1-8 alkyl substituted with a group selected from CycA or—NHC(O)-CycA,

[0346] (6) C2-8 alkenyl substituted with CycA or

[0347] (7) C2-8 alkynyl substituted with CycA,

[0348] wherein CycA may be substituted with 1-5 of R^(27a), and

[0349] R^(27a), is (1) C1-8 alkyl,

[0350] (2) halogen,

[0351] (3) —NR¹¹R¹²,

[0352] (4) —OR¹³,

[0353] (5) phenyl,

[0354] (6) nitro,

[0355] (7) CF₃,

[0356] (8) cyano,

[0357] (9) tetrazole,

[0358] (10) —SR¹⁴,

[0359] (11) —COR¹⁵,

[0360] (12) oxo or

[0361] (13) C1-8 alkyl substituted with 1-5 of group selected from thefollowing (a) to (k):

[0362] (a) halogen, (b) —NR¹¹R¹², (c) —OR¹³, (d) phenyl, (e) nitro, (f)CF₃, (g) cyano, (h) tetrazole, (j) —SR¹⁴, (k) —COR¹⁵, or

[0363] [II] (a) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substitutedwith a group selected from halogen, CF₃, nitro, cyano or NR¹⁸R¹⁹ or

[0364] (b) (1) CycA containing 1-5 of substituent R²⁷ or

[0365] (2) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted withCycA, which contains 1-5 of substituent R²⁷,

[0366] wherein at least one of R²⁷ described in (1) and (2) is selectedfrom

[0367] (i) a C5-10 mono- or bi-cyclic carboring,

[0368] (ii) a 5-10 membered mono- or bi-cyclic heteroring,

[0369] (iii) —SO₂R¹⁵, (iv) —OCF₃ or

[0370] (v) C1-8 alkyl substituted with 1-5 of the group selected from(a) halogen, (b) —NR¹¹R¹², (c) —OR¹³, (d) a C5-10 mono-or bi-cycliccarboring, (e) nitro, (f) CF₃, (g) cyano, (h) a 5-10 membered mono- orbi-cyclic heteroring, (j) —SR¹⁴, (k) —COR¹⁵, (1) —SO₂R¹⁵ and (m) —OCF₃(at least one is a C5-10 mono-or bi-cyclic carboring, a 5-10 mono- orbi-cyclic heteroring, —SO₂R¹⁵ or —OCF₃))

[0371] Particularly preferably,

[0372] [I] (1) C1-8 alkyl,

[0373] (2) C2-8 alkenyl,

[0374] (3) C2-8 alkynyl,

[0375] (4) CycA or

[0376] (5) C1-8 alkyl substituted with a group selected from CycA or—NHC(O)-CycA,

[0377] (6) C2-8 alkenyl substituted with CycA or

[0378] (7) C2-8 alkynyl substituted with CycA,

[0379] wherein CycA is a mono- or bi-cyclic C5-10 carboaryl which may besubstituted with 1-5 of R²⁷ or partially or completely saturated onethereof, or mono- or bi-cyclic 5-10 membered heteroaryl containing 1-2of nitrogen, 1-2 of oxygen and/or 1 of sulfur atom, or partially orcompletely saturated one thereof or

[0380] [II] (a) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substitutedwith a group selected from halogen atom, CF₃, nitro, cyano and NR¹⁸R¹⁹,or

[0381] (b) CycA containing 1-5 of substituent R²⁷ or

[0382] (2) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted withCycA, which contains 1-5 of substituent R²⁷,

[0383] wherein at least one of R²⁷ described in (1) and (2) is selectedfrom

[0384] (i) a C5-10 mono- or bi-cyclic carboring,

[0385] (ii) a 5-10 membered mono- or bi-cyclic heteroring,

[0386] (iii) —SO₂R¹⁵, (iv) —OCF₃ or

[0387] (v) C1-8 alkyl substituted with 1-5 of group selected from (a)halogen, (b) —NR¹¹R¹², (c) —OR¹³, (d) a C5-10 mono- or bi-cycliccarboring, (e) nitro, (f) CF₃, (g) cyano, (h) a 5-10 membered mono- orbi-cyclic heteroring, (j) —SR¹⁴, (k) —COR¹⁵, (1) —SO₂R¹⁵ and (m) OCF₃,wherein at least one group is selected from a C5-10 mono- or bi-cycliccarboring or a 5-10 membered mono- or bi-cyclic heteroring, —SO₂R¹⁵ orOCF₃,

[0388] above CycA is C5-10 mono- or bi-cyclic carboaryl or partially orcompletely saturated one, or 5-10 membered mono- or bi-cyclic heteroarylcontaining 1-2 of nitrogen, 1-2 of oxygen and/or 1 of sulfur, orpartially or completely saturated one thereof.

[0389] Particularly preferably, [I] (1) C1-4 alkyl, (2) C2-4 alkenyl,(3) C2-4 alkynyl, (4) CycA or (5) C1-4 alkyl, C2-4 alkenyl or C2-4alkynyl substituted with CycA which is preferably cyclopentane,cyclohexane, benzene, naphthalene, pyrrolidine, piperidine, piperazine,morpholine, pyrrole, furan, thiophene, pyridine, pyrimidine, pyrazine,pyridazine, indole, isoindole, quinoline, isoquinoline, quinazoline,quinoxaline, phthalazine, benzothiophene, benzofuran, benzoxazole,tetrahydroquinoline, tetrahydroquinazoline, tetrahydroquinoxaline,optionally substituted with 1-5 of R^(27a) or

[0390] [II] (a) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substitutedwith a group selected from halogen, CF₃, nitro, cyano or NR¹⁸R¹⁹ or

[0391] (b) (1) CycA which contains 1-5 of substituent R²⁷, or

[0392] (2) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted withCycA which contains 1-5 of substituent R²⁷,

[0393] wherein at least one of R²⁷ described in (1) and (2) is selectedfrom

[0394] (i) a C5-10 mono- or bi-cyclic carboring,

[0395] (ii) a 5-10 membered mono- or bi-cyclic heteroring,

[0396] (iii) —SO₂R⁵, (iv) —OCF₃, or

[0397] (v) C1-8 alkyl substituted with 1-5 of group selected from (a)halogen atom, (b) —NR¹¹R¹², (c) —OR¹³, (d) a C5-10mono- or bi-cycliccarboring, (e) nitro, (f) CF₃, (g) cyano, (h) a 5-10 membered mono- orbi-cyclic heteroring, (j) —SR¹⁴, (k) —COR¹⁵, (1) —SO₂R¹⁵ or (m) —OCF₃,wherein at least one group is selected from a C5-10 mono- or bi-cycliccarboring, a 5-10 membered mono- or bi-cyclic heteroring, —SO₂R¹⁵ or—OCF₃, and

[0398] CycA is preferably cyclopentane, cyclohexane, benzene,naphthalene, pyrrolidine, piperidine, piperazine, morpholine, pyrrole,furan, thiophene, pyridine, pyrimidine, pyrazine, pyridazine, indole,isoindole, quinoline, isoquinoline, quinazoline, quinoxaline,phthalazine, benzothiophene, benzofuran, benzoxadiazole,tetrahydroquinoline, tetrahydroquinazoline, or tetrahydroquinoxaline.

[0399] In the formula (I), AA¹ is preferably a single bond,

[0400] which is formed with R, but more preferably, AA¹ is a single bondor

[0401] Any group represented by R¹ is preferable, but more preferably,R¹ is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with NH₂,C1-4 alkoxy, SH, SCH₃, phenyl, hydroxyphenyl, COOH, CONH₂, guanidino,imidazole or indole. Particularly preferably, R¹ is hydrogen, C1-8alkyl, phenyl or C1-8 alkyl substituted with C1-4 alkoxy or phenyl.Then, any group represented by R² is preferable, but hydrogen isparticularly preferable.

[0402] And C3-6 alkylene which R¹ and R² together form is alsopreferable.

[0403] Any group represented by R³ is preferable, but more preferably R³is hydrogen or C1-4 alkyl.

[0404] And C2-4 alkylene which R³ and R¹ together form is alsopreferable.

[0405] In the formula (I), any group represented by AA² is allpreferable, but more preferably, AA² is a single bond,

[0406] Particularly preferably, AA² is a single bond,

[0407] Any group represented by R⁴ is preferable, but more preferably,R⁴ is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with NH₂,C1-4 alkoxy, SH, SCH₃, phenyl, hydroxyphenyl, COOH, CONH₂, guanidino,imidazole or indole. Particularly preferably, R⁴ is hydrogen, C1-8alkyl, phenyl or C1-8 alkyl substituted with C1-4 alkoxy or phenyl.Then, any group represented by R⁵ is preferable, and hydrogen isparticularly preferable.

[0408] And C3-6 alkylene which R⁴ and R⁵ together form is alsopreferable.

[0409] Any group represented by R⁶ is preferable, but more preferably R⁶is hydrogen or C1-4 alkyl.

[0410] And C2-4 alkylene which R⁶ and R⁴ together form is alsopreferable.

[0411] Any group represented by R⁴⁸ is preferable, but more preferably,R⁴⁸ is

[0412] [I] hydrogen, C1-4 alkyl, phenyl or C1-4 alkyl substituted withphenyl, or

[0413] [II] C2-6 alkylene, wherein one carbon atom may be replaced byoxygen, sulfur or —NR⁴⁷—, wherein R⁴⁷ is hydrogen or C1-4 alkyl to beformed together with R⁴, when AA¹ is a single bond. Particularlypreferably, R⁴⁸ is [I] hydrogen atom or C1-4 alkyl, or

[0414] [II] when AA¹ is a single bond, taken together with R to formtetramethylene, pentamethylene, —CH₂—CH₂—O—CH₂—CH₂—,—CH₂—CH₂—NH—CH₂—CH₂— or —CH₂—CH₂—N(CH₃)—CH₂—CH₂—.

[0415] In the formula (I), any group which AA¹ and AA² together form ispreferable, but preferably, it is

[0416] particularly preferably, it is

[0417] Any group represented by R⁷ is preferable. More preferably, R⁷ ishydrogen atom, C1-8 alkyl, phenyl, or C1-8 alkyl substituted with NH₂,C1-4 alkoxy, SH, SCH₃, phenyl, hydroxyphenyl, COOH, CONH₂, guanidino,imidazole or indole.

[0418] Particularly preferably, R⁷ is hydrogen, C1-8 alkyl, phenyl, orC1-8 alkyl substituted with C1-4 alkoxy or phenyl. Then, any grouprepresented by R⁸ is preferable, but hydrogen is most preferable.

[0419] And C3-6 alkylene which R⁷ and R⁸ together form is alsopreferable.

[0420] Any group represented by R⁹ is preferable, but more preferably R⁹is hydrogen or C1-4 alkyl.

[0421] And C2-4 alkylene which R⁹ and R⁷ together form is alsopreferable.

[0422] Any group represented by R¹⁰ is preferable, but more preferablyR¹⁰ is C1-6 alkyl, C2-4 alkenyl, CycA or C1-6 alkyl or C2-4 alkenylsubstituted with COR⁷¹, NR⁷²R⁷³, hydroxy, OR⁷⁴ or CycA, particularlypreferably C1-4 alkyl, or C1-4 alkyl substituted with phenyl, NR⁷²R⁷³ orC3-6 cycloalkyl.

[0423] Any group represented by R¹⁰ is preferable, but more preferablyR¹⁰ is C1-6 alkyl, CycA or C1-6 alkyl substituted with COR⁷¹, NR⁷²R⁷³,hydroxy, OR⁷⁴ or CycA, more preferably C1-4 alkyl, C2-4 alkenyl, or C1-4alkyl or C2-4 alkenyl substituted with phenyl, NR⁷²R⁷³, C3-6 cycloalkyl,piperidine or pyrrolidine.

[0424] is preferably,

[0425] and more preferably,

[0426] In the ring represented by

[0427] the C5-8 carbocycle which is a condensed ring of the ringsrepresented by

[0428] or 5-8 membered heteroring which contains 1 or 2 of nitrogen, 1of oxygen and/or 1 of sulfur atom, are all preferable, but morepreferably, C5-6 carboring or 5-6 membered heteroring containing 1 or 2of nitrogen, 1 of oxygen and/or 1 of sulfur atom, concretely,cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene,cyclohexadiene, benzene, pyridine, piperidine, pyrrole, pyrrolidine,furan, dioxane, dioxole, pyran, thiophene, thian, thiepine, oxathiolane,oxazolidine, pyrazole, oxazole, pyrazine, pyrimidine, pyridazine.

[0429] R⁸³ is preferably hydrogen atom, C1-4 alkyl, or C1-4 alkylsubstituted with Cyc, cyano, —OR⁶⁹ or —COR⁶⁸, and more preferably C1-4alkyl or C1-4 alkyl substituted with Cyc.

[0430] R¹⁰ is preferably —OR⁷⁴, more preferably hydroxy, C1-4 alkoxy, orC1-4 alkoxy substituted with phenyl.

[0431] In the compounds of formula (I), the following compounds arepreferred;

[0432] the compound of (I-1A)

[0433] wherein all symbols have the same meanings as above, the compoundof formula (I-2A)

[0434] wherein all symbols have the same meanings as above, the compoundof formula (I-3A)

[0435] wherein all symbols have the same meanings as above, the compoundof formula (I-4A)

[0436] wherein all symbols have the same meanings as above, the compoundof formula (I-5A)

[0437] wherein all symbols have the same meanings as above, the compoundof formula (I-6A)

[0438] wherein all symbols have the same meanings as above, the compoundof formula (I-7A)

[0439] wherein all symbols have the same meanings as above, the compoundof formula (I-8A)

[0440] wherein all symbols have the same meanings as above, the compoundof formula (I-9A)

[0441] wherein all symbols have the same meanings as above, the compoundof formula (I-10A)

[0442] wherein all symbols have the same meanings as above, the compoundof formula (I-1B)

[0443] wherein all symbols have the same meanings as above, the compoundof formula (I-2B)

[0444] wherein all symbols have the same meanings as above, the offormula (I-3B)

[0445] wherein all symbols have the same meanings as above, the compoundof formula (I-1C)

[0446] wherein all symbols have the same meanings as above, the compoundof formula (I-2C)

[0447] wherein all symbols have the same meanings as above, the compoundof formula (I-3C)

[0448] wherein all symbols have the same meanings as above, the compoundof formula (I-4C)

[0449] wherein all symbols have the same meanings as above, the compoundof formula (I-5C)

[0450] wherein all symbols have the same meanings as above, the compoundof formula (I-6C)

[0451] wherein all symbols have the same meanings as above, the compoundof formula (I-7C)

[0452] wherein all symbols have the same meanings as above, the compoundof formula (I-8C)

[0453] wherein all symbols have the same meanings as above, the compoundof formula (I-9C)

[0454] wherein all symbols have the same meanings as above, the compoundof formula (I-10C)

[0455] wherein all symbols have the same meanings as above, the compoundof formula (I-1D)

[0456] wherein all symbols have the same meanings as above, and thecompound of formula (I-2D)

[0457] wherein all symbols have the same meanings as above.

[0458] Particularly, the compounds described in the following tables 1to 30 and the compounds described in the examples or non-toxic saltsthereof are preferable. In the following tables, all symbols have thesame meanings as above. TABLE 1 (I-1A-1)

No. R²⁷ 1 3-F 2 2-CN 3 3-CN 4 3-NO₂ 5 4-NO₂ 6 3-CH₃ 7 2-CH₂—Cl 84-CH₂—Cl 9 4-CH₂CH₃ 10 4-(CH₂)₃CH₃ 11 4-N(CH₃)₂ 12 4-OCH₂CH₃ 132,3-di-CH₃ 14 3,5-di-F 15 3,4-di-F 16 2-OCF₃ 17 3-OCF₃ 18 4-CONH₂ 193-CONH₂ 20 4-COOH 21 4-OCH₂COOH 22 4-O(CH₂)₅CH₃ 23 4-CH₂CH(CH₃)₂ 243-COOH 25 3-OCH₂COOH 26 3-O(CH₂)₅CH₃ 27 3-CH₂CH(CH₃)₂ 28 2-OCH₂COOH 292-O(CH₂)₅CH₃ 30 2-CH₂CH(CH₃)₂

[0459] TABLE 2 (I-2A-1)

No. R¹⁶ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

[0460] TABLE 3 (I-3A-1)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

[0461] TABLE 4 (I-4A-1)

No. R⁷ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

[0462] TABLE 5 (I-5A-1)

No. R⁷⁴ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

[0463] TABLE 6 (I-6A-1)

No. R⁷⁴ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

[0464] TABLE 7 (I-1B-1)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

[0465] TABLE 8 (I-2B-1)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

[0466] TABLE 9 (I-1C-1)

No. R²⁷ 1 3-F 2 2-CN 3 3-CN 4 3-NO₂ 5 4-NO₂ 6 3-CH₃ 7 2-CH₂—Cl 84-CH₂—Cl 9 4-CH₂CH₃ 10 4-(CH₂)₃CH₃ 11 4-N(CH₃)₂ 12 4-OCH₂CH₃ 132,3-di-CH₃ 14 3,5-di-F 15 3,4-di-F 16 2-OCF₃ 17 3-OCF₃ 18 4-CONH₂ 193-CONH₂ 20 4-COOH 21 4-OCH₂COOH 22 4-O(CH₂)₅CH₃ 23 4-CH₂CH(CH₃)₂ 243-COOH 25 3-OCH₂COOH 26 3-O(CH₂)₅CH₃ 27 3-CH₂CH(CH₃)₂ 28 2-OCH₂COOH 292-O(CH₂)₅CH₃ 30 2-CH₂CH(CH₃)₂

[0467] TABLE 10 (I-2C-1)

No. R¹⁶ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

[0468] TABLE 11 (I-3C-1)

No.

No.

1

10

2

11

3

12

4

13

5

14

6

15

7

16

8

17

9

18

[0469] TABLE 12 (I-4C-1)

No. R⁷ No. R⁷ 1

12

2

13

3

14

4

15

5

16

6

17

7

18

8

19

9

20

10

21

11

22

[0470] TABLE 13 (I-5C-1)

No. R⁷⁴ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

[0471] TABLE 14 (I-6C-1)

No. R⁷⁴ No. R⁷⁴ 1

13

2

14

3

15

4

16

5

17

6

18

7

19

8

20

9

21

10

22

11

23

12

[0472] TABLE 15 (I-1D-1)

No. R⁸³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

[0473] TABLE 16 (I-2D-1)

No. R⁸³ No. R⁸³ 1

13

2

14

3

15

4

16

5

17

6

18

7

19

8

20

9

21

10

22

11

23

12

[0474] TABLE 17 (I-7A-1)

No. R²⁷ No. R²⁷ 1 3-F 16 2-OCF₃ 2 2-CN 17 3-OCF₃ 3 3-CN 18 4-CONH₂ 43-NO₂ 19 3-CONH₂ 5 4-NO₂ 20 4-COOH 6 3-CH₃ 21 4-OCH₂COOH 7 2-CH₂—Cl 224-O(CH₂)₅CH₃ 8 4-CH₂—Cl 23 4-CH₂CH(CH₃)₂ 9 4-CH₂CH₃ 24 3-COOH 104-(CH₂)₃CH₃ 25 3-OCH₂COOH 11 4-N(CH₃)₂ 26 3-O(CH₂)₅CH₃ 12 4-OCH₂CH₃ 273-CH₂CH(CH₃)₂ 13 2,3-di-CH₃ 28 2-OCH₂COOH 14 3,5-di-F 29 2-O(CH₂)₅CH₃ 153,4-di-F 30 2-CH₂CH(CH₃)₂

[0475] TABLE 18 (I-8A-1)

No. R¹⁶ No. R¹⁶ 1

11

2

12

3

13

4

14

5

15

6

16

7

17

8

18

9

19

10

[0476] TABLE 19 (I-9A-1)

No. R⁷ No. R⁷ 1

12

2

13

3

14

4

15

5

16

6

17

7

18

8

19

9

20

10

21

11

22

[0477] TABLE 20 (I-10A-1)

No. R⁷⁴ No. R⁷⁴ 1

13

2

14

3

15

4

16

5

17

6

18

7

19

8

20

9

21

10

22

11

23

12

[0478] TABLE 21 (I-3B-1)

No.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

[0479] TABLE 22 (I-7C-1)

No. R²⁷ No. R²⁷ 1 3-F 16 2-OCF₃ 2 2-CN 17 3-OCF₃ 3 3-CN 18 4-CONH₂ 43-NO₂ 19 3-CONH₂ 5 4-NO₂ 20 4-COOH 6 3-CH₃ 21 4-OCH₂COOH 7 2-CH₂—Cl 224-O(CH₂)₅CH₃ 8 4-CH₂—Cl 23 4-CH₂CH(CH₃)₂ 9 4-CH₂CH₃ 24 3-COOH 104-(CH₂)₃CH₃ 25 3-OCH₂COOH 11 4-N(CH₃)₂ 26 3-O(CH₂)₅CH₃ 12 4-OCH₂CH₃ 273-CH₂CH(CH₃)₂ 13 2,3-di-CH₃ 28 2-OCH₂COOH 14 3,5-di-F 29 2-O(CH₂)₅CH₃ 153,4-di-F 30 2-CH₂CH(CH₃)₂

[0480] TABLE 23 (I-8C-1)

No. R¹⁶ No. R¹⁶ 1

11

2

12

3

13

4

14

5

15

6

16

7

17

8

18

9

19

10

[0481] TABLE 24 (I-9C-1)

No. R⁷ No. R⁷ 1

12

2

13

3

14

4

15

5

16

6

17

7

18

8

19

9

20

10

21

11

22

[0482] TABLE 25 (I-10C-1)

No. R⁷⁴ No. R⁷⁴ 1

13

2

14

3

15

4

16

5

17

6

18

7

19

8

20

9

21

10

22

11

23

12

[0483] TABLE 26 (I-3D-1)

No. R⁸³ 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

[0484] TABLE 27 (I-7A-2)

No. R²⁷ 1 2-CH₂N(CH₃)₂ 2 3-CH₂N(CH₃)₂ 3 4-CH₂N(CH₃)₂ 4

5

6

7

8

9

[0485] TABLE 28 (I-7C-2)

No. R²⁷ 1 2-CH₂N(CH₃)₂ 2 3-CH₂N(CH₃)₂ 3 4-CH₂N(CH₃)₂ 4

5

6

7

8

9

[0486] TABLE 29 (I-11A-1)

No. R—AA1—AA2 1

2

3

4

5

6

[0487] TABLE 30 (I-11C-1)

No. R—AA1—AA2 1

2

3

4

5

6

[0488] The Methods for the Preparation of the Compound of the PresentInvention

[0489] (1) Among the compounds of formula (I), the compound wherein AA¹and AA² represent a single bond at the same time, none of R, R⁷, R⁸, R¹⁰

[0490] contains carboxy, hydroxy, amino, thiol, guanidino, amidino orphosphono, and R does not represent hydrogen, i.e. the compound offormula (IA)

[0491] wherein R^(A), R^(7A), R^(8A) and R^(10A) and

[0492] have the same meanings as R, R⁷, R⁸, R¹⁰ and

[0493] respectively, with proviso that none of them contains carboxy,hydroxy, amino, thiol, guanidino, amidino or phosphono and R^(A) doesnot represent hydrogen, may be prepared by subjecting to a reaction acompound of formula (IIA)

[0494] wherein X is halogen atom or a leaving group such as mesyl andtosyl and the other symbols have the same meanings as above, and acompound of formula (IIB)

[0495] wherein all symbols have the same meanings as above. The reactionof the compound of formula (IIA) and the compound of formula (IIB) is,for example, carried out in an organic solvent (dimethylformamide,acetonitrile, etc.) in the presence or absence of a tertiary amine(triethylamine, N-methylmorpholine, diisopropylethylamine, etc.), a base(sodium hydride etc.), an alkali (potassium carbonate, sodium carbonate,etc.) or fluoride (sodium fluoride, potassium fluoride, cesium fluoride,etc.) at a temperature of 20 to 40° C.

[0496] [2] Among the compounds of formula (I), wherein AA¹ and AA² are asingle bond at the same time, R is hydrogen and none of R⁷, R⁸, R¹⁰ and

[0497] contains carboxy, hydroxy, amino, thiol, guanidino, amidino,phosphono, i.e. the compound of formula (IB)

[0498] wherein all symbols have the same meanings as above, may beprepared by subjecting to a deprotection reaction the compound, amongthe compounds of formula (IA), wherein R^(A) is a protective group ofamino, i.e. the compound of formula (IA-1)

[0499] wherein R^(A-1) is a protective group of amino and the othersymbols have the same meanings as above.

[0500] As protective groups for amino group, for example,benzyloxycarbonyl, t-butoxycarbonyl, trifluoroacetyl,9-fluorenylmethoxycarbonyl may be included, but other groups that can beeasily and selectively eliminated may also be used instead. For example,the groups described in T. W. Greene, Protective Groups in OrganicSynthesis, Wiley, New York, 1991 may be used.

[0501] Deprotection reaction for protective groups of amino group isknown, for example,

[0502] 1) deprotection reaction under alkaline conditions,

[0503] 2) deprotection reaction under acidic conditions,

[0504] 3) deprotection reaction by hydration, etc. may be included.

[0505] To explain these methods concretely,

[0506] 1) deprotection reaction under alkaline conditions is carriedout, for example, in an organic solvent (methanol, tetrahydrofuran,dioxane, dimethylformamide, etc.) using a hydroxide of alkali metals(sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.),hydroxide of alkaline earth metals (barium hydroxide, calcium hydroxide,etc.), organic amine (triethylamine, N-methylmorpholine,diisopropylethylamine, piperidine, etc.) or a quaternary ammonium salt(tetrabutyl ammonium fluoride etc.) or a solution thereof or a mixturethereof at a temperature of 0 to 40° C.;

[0507] 2) deprotection reaction under acidic conditions is carried out,for example, in an organic solvent (methylene chloride, chloroform,dioxane, ethyl acetate, anisole, etc.), using organic acid (acetic acid,trifluoroacetic acid, methanesulfonic acid, etc.) or inorganic acid(hydrochloric acid, sulfuric acid, etc.) or a mixture thereof(hydrobromic acid/acetic acid, etc.) at a temperature of 0 to 100° C.;

[0508] 3) deprotection reaction by hydration is, for example, carriedout in a solvent (ethers (tetrahydrofuran, dioxane, dimethoxyethane,diethyl ether, etc.), alcohols (methanol, ethanol, etc.), benzenes(benzene, toluene, etc.), ketones (acetone, methyl ethyl ketone, etc.),nitriles such as acetonitrile, amides such as dimethylformamide, water,ethyl acetate, acetic acid or a mixture of more than two from above,etc.) in the presence of a catalyst (palladium-carbon, palladium black,palladium hydroxide, platinum oxide, Raney nickel, etc.) under theatmosphere of hydrogen of normal or suppressed pressure, or in thepresence of ammonium formate at a temperature of 0 to 200° C.

[0509] As easily understood by those skilled in the art, the compoundsof the present invention may be easily prepared by selecting thesereactions.

[0510] [3] Among the compounds of formula (I), wherein AA¹ and AA² are asingle bond at the same time, and at least one of R, R⁷, R⁸, R¹⁰ or

[0511] contains carboxy, hydroxy, amino, thiol, guanidino, amidino,phosphono or R is hydrogen, i.e. the compound of formula (IC)

[0512] wherein R^(C), R^(7C), R^(8C), R^(10C) and

[0513] have the same meanings as R, R⁷, R⁸, R¹⁰ and

[0514] respectively, with proviso that at least one contains carboxy,hydroxy, amino, thiol, guanidino, amidino, phosphono or R is hydrogen,may be prepared by subjecting to deprotection reaction of protectivegroups of carboxy, hydroxy, amino, thiol, guanidino, amidino orphosphono, the compound among the compounds of formula (IA) prepared bya previous method, wherein at least one of R^(A), R^(7A), R^(8A),R^(10A) or

[0515] contains a protected form of carboxy, hydroxy, amino, thiol,guanidino, amidino or phosphono, i.e. the compound of formula (IA-2)

[0516] wherein R^(A-2), R^(7A-2) , R^(8A-2), R^(10A-2)

[0517] have the same meanings as R^(A), R^(7A), R^(8A), R^(10A) and

[0518] respectively, with proviso that at least one of R^(A-2),R^(7A-2), R^(8A-2), R^(10A-2) and

[0519] is a protected form of carboxy, hydroxy, amidno, thiol,guanidino, amidino or phosphono, or R^(A-2) is a protective group ofamino, and the other symbols have the same meanings as above, or thecompound among the compounds of formula (IB) prepared by a method abovedescribed, wherein at least one group is a protected form of carboxy,hydroxy, amino, thiol, guanidino, amidino or phosphono, i.e. thecompound of formula (IB-1)

[0520] wherein all symbols have the same meanings as above.

[0521] Protective groups for carboxy include, for example, methyl,ethyl, t-butyl and benzyl.

[0522] Protective groups for hydroxy include, for example,methoxymethyl, 2-tetrahydropyranyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, acetyl and benzyl.

[0523] Protective groups for amino include the ones shown above.

[0524] Protective groups for thiol include, for example, benzyl,methoxybenzyl, methoxymethyl, 2-tetrahydropyranyl, diphenylmethyl andacetyl.

[0525] Protective groups for guanidino and amidino include, for example,benzyloxycarbonyl, t-butoxycarbonyl and 9-fluorenylmethoxycarbonyl.

[0526] Protective groups for phosphono include, for example, C1-2 alkyl,phenyl, benzyl, 2,2,2-trichloroethyl and cyanoethyl.

[0527] As to protective groups for carboxy, hydroxy, amino, thiol,guanidino, amidino or phosphono group, other groups than above listedmay also be used instead, if easily and selectively eliminated. Forexample, the groups described in T. W. Greene, Protective Groups inOrganic Synthesis, Wiley, New York, 1991 may be used.

[0528] Deprotection reactions of the protective groups of carboxy,hydroxy, amino, thiol, guanidino or amidino are well known, for example,

[0529] 1) a deprotection reaction under alkaline conditions,

[0530] 2) a deprotection reaction under acidic conditions,

[0531] 3) a deprotection reaction by hydration,

[0532] 4) a deprotection reaction of silyl-containing groups, etc. maybe included.

[0533] The methods of 1), 2) and 3) are carried out by the methodsdescribed above.

[0534] 4) A deprotection reaction of silyl-containing group is carriedout, for example, in a water-miscible organic solvent (tetrahydrofuran,acetonitrile, etc.) using tetrabutylammonium fluoride at a temperatureof 0 to 40° C.

[0535] Deprotection reaction of protective groups of phosphono is known,for example,

[0536] (a) Elimination of C1-2 alkyl is carried out in an organicsolvent such as chloroform using halogenated trimethylsilyl(chlorotrimethylsilyl, bromotrimethylsilyl, iodotrimethylsilyl, etc.) asa reagent, in the presence or absence of alkali metal iodide (sodiumiodide, potassium iodide, etc.) at a temperature of 0 to 40° C.

[0537] (b) Elimination of phenyl is carried out under atmosphere ofhydrogen in an organic solvent (methanol, ethanol, tetrahydrofuran,etc.) or without a solvent in the presence or absence of a catalyst suchas platinum oxide and an organic acid such as acetic acid or aninorganic acid such as hydrochloric acid at a temperature of 0 to 50° C.for 24 hours to 3 days.

[0538] (c) Elimination of benzyl is carried out under atmosphere ofhydrogen in an organic solvent (methanol, ethanol, tetrahydrofuran,pyridine, acetic acid, etc.) in the presence of a catalyst(palladium-carbon, palladium black, palladium hydroxide, etc.) at atemperature of 0 to 50° C.

[0539] (d) Elimination of 2,2,2-trichloroethyl is carried out in anorganic solvent (methanol, ethanol, tetrahydrofuran, etc.) or without asolvent using a micropowder of zinc and others and an organic acid suchas acetic acid or an inorganic acid such as hydrochloric acid at atemperature of 0 to 50° C.

[0540] (e) Elimination of cyanoethyl is carried out in a solvent (water,methanol, ethanol, tetrahydrofuran, pyridine, etc.) or without asolvent, in the presence of a base (triethylamine, dimethylamine,t-butylamine, etc.) at a temperature of 0 to 100° C.

[0541] As easily understood by those skilled in the art, the targetcompounds of the present invention may be easily prepared by selectingthese reactions.

[0542] [4] Among the compounds of formula (I), wherein AA¹ and AA² donot represent a single bond at the same time, and none of R, AA¹, AA²,R⁷ R⁸, R¹⁰ and

[0543] contains carboxy, hydroxy, amino, thiol, guanidino, amidino,phosphono, i.e. the compound of formula (ID)

[0544] wherein AA^(1A) and AA^(2A) have the same meanings as AA¹ andAA², with proviso that no group contains carboxy, hydroxy, amino, thiol,guanidino, amidino, phosphono, and AA^(1A) and AA^(2A) do not representa single bond at the same time, and the other symbols have the samemeanings as above, may be prepared according to the following method of(A) or (B).

[0545] (A) The compound of formula (ID) may be prepared by subjecting toamidation reaction the compound of formula (IIC)

R^(A)-AA^(1A)-AA^(2A)—OH  (IIC),

[0546] wherein all symbols have the same meanings as above, and thecompound of formula (IB) above described.

[0547] Amidation reaction is known, for example,

[0548] 1) a method using acid halide,

[0549] 2) a method using mixed anhydride,

[0550] 3) a method using a condensing agent (EDC, DCC, etc.), etc.

[0551] To explain these methods concretely,

[0552] 1) the method using acid halide is carried out, for example, bysubjecting to a reaction carboxylic acid and acid-halogenating agent(oxalyl chloride, thionyl chloride, etc.) in an organic solvent(chloroform, methylene chloride, diethyl ether, tetrahydrofuran, etc.)or without a solvent, at a temperature between −20° C. and refluxingtemperature, and then subjecting to a reaction thus obtained acid halidein the presence of tertiary amine (pyridine, triethylamine,dimethylaniline, dimethylaminopyridine, etc.) in an inert organicsolvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran,etc.) at a temperature between 0 to 40° C.

[0553] And it may be carried out by subjecting to a reaction with acidhalide in an organic solvent (dioxane, tetrahydrofuran, etc.) using anaqueous alkali solution (an aqueous solution of sodium bicarbonate orsodium hydroxide, etc.) at a temperature between 0 to 40° C.

[0554] 2) The method using mixed anhydride is carried out, for example,by subjecting to a reaction in an organic solvent (chloroform, methylenechloride, diethyl ether, tetrahydrofuran, etc.) or without a solvent, inthe presence of tertiary amine (pyridine, triethylamine,dimethylaniline, dimethylaminopyridine, etc.), carboxylic acid with acidhalide (pivaloyl chloride, tosyl chloride, mesylchloride, etc.) or acidderivative (chloroethyl formate, chloroisobutyl formate, etc.) at atemperature between 0 to 40° C., and then subjecting to a reaction thusobtained mixed anhydride with amine in an organic solvent (chloroform,methylene chloride, diethyl ether, tetrahydrofuran, etc.) at atemperature between 0 to 40° C.

[0555] 3) The method using a condensing agent is carried out, forexample, in an organic solvent (chloroform, methylene chloride,dimethylformamide, diethyl ether, tetrahydrofuran, etc.) or without asolvent, in the presence or absence of a tertiary amine (pyridine,triethylamine, dimethylaniline, dimethylaminopyridine, etc.), using acondensing agent (1,3-dicychlorohexylcarbodiimide (DCC),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDC),1,1′-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodide,etc.) in the presence or absence of 1-hydroxybenzotriazole (1-HOBt), bysubjecting to a reaction carboxylic acid and amine at a temperaturebetween 0 and 40° C.

[0556] The reactions 1), 2) and 3) are desirably carried out underatmosphere of inert gas (argon, nitrogen, etc.) and anhydrousconditions.

[0557] (B) The compound of formula (ID) may be prepared by subjecting toa reaction the compound of formula (IID)

[0558] wherein all symbols have the same meanings as above, and thecompound of formula (IIB) above described. The reaction of the compoundof formula (IID) and the compound of formula (IIB) is carried outaccording to the same method of the reaction of the compound of formula(IIA) and the compound of formula (IIB) above described.

[0559] [5] Among the compounds of formula (I), wherein AA¹ and AA² donot represent a single bond at the same time, and at least one of R,AA¹, AA², R⁷, R⁸, R¹⁰ and

[0560] represents a group which contains carboxy, hydroxy, amino, thiol,guanidino, amidino or phosphono, i.e. the compound of formula (IE)

[0561] wherein R^(E), AA^(1E), AA^(2E), R^(7E), R^(8E), R^(10E) and

[0562] have the same meanings as R, AA¹, AA², R⁷, R⁸, R¹⁰ and

[0563] respectively, with proviso that at least one of them containscarboxy, hydroxy, amino, thiol, guanidino, amidino or phosphono, orR^(E) is hydrogen, and the other symbols have the same meanings asabove, may be prepared by subjecting to a deprotection reaction ofprotective group of carboxy, hydroxy, amino, thiol, guanidino, amidinoor phosphono, the compound among the compounds of formula (ID), whichcontains at least one protected form of carboxy, hydroxy, amino, thiol,guanidino, amidino or phosphono, i.e. the compound of formula (ID-1)

[0564] wherein R^(A-3), AA^(1A-3) , AA^(2A-3), R^(7A-3), R^(8A-3),R^(10A-3) and

[0565] have the same meanings as R^(A), AA^(1A), AA^(2A), R^(7A),R^(8A), R^(10A) and

[0566] respectively, with proviso that at least one of R^(A-3),AA^(1A-3), AA^(2A-3), R^(7A-3), R^(8A-3), R¹⁰⁻³ and

[0567] contains at least one protected form of carboxy, hydroxy, amino,thiol, guanidino, amidino or phosphono or R^(A-3) is a protected form ofamino, and the other symbols have the same meanings as above.

[0568] Deprotection reaction of the protective groups of carboxy,hydroxy, amino, thiol, guanidino, amidino or phosphono is carried outaccording to the method described above.

[0569] The compound of formula (IA) above described may also be preparedby subjecting the compound of formula (IB) to a reaction of (A)amidation, (B) sulfonamideation, (C) forming an urea, (D) forming anurethane, (E) N-alkylation.

[0570] (A) Amidation Reaction is Carried out by Subjecting to a Reactionthe Compound of Formula (IB) and the Compound of Formula (IIE-A)

[0571] wherein R^(16A) has the same meaning as R¹⁶, but R^(16A)represents a group which does not contain carboxy, hydroxy, amino,thiol, guanidino or amidino. Amidation reaction is carried out accordingto the method described above.

[0572] (B) Sulfonamidation Reaction is Carried out by Subjecting to aReaction the Compound of Formula (IB) and the Compound of Formula(IIE-B)

[0573] wherein X^(B) is halogen and the other symbols are the samemeanings as above.

[0574] Sulfonamidation reaction is known, for example, it is carried outby subjecting sulfonic acid to a reaction with acid halide (oxalylchloride, thionyl chloride, etc.) at a temperature of −20° C. torefluxing temperature in an inert organic solvent (chloroform, methylenechloride, diethyl ether, tetrahydrofuran, etc.) or without a solvent,followed by subjecting thus obtained sulfonyl halide to a reaction withamine in the presence of tertiary amine (pyridine, triethylamine,dimethylaniline, dimethylaminopyridine, etc.) in an inert organicsolvent (chloroform, methylene chloride, diethyl ether, tetrahydrofuran,etc.) at a temperature of 0 to 40° C.

[0575] (C) A Reaction to Form Urea is Carried out According to theFollowing Method of (1) or (2).

[0576] (1) A Method of Subjecting to a Reaction the Compound of Formula(IB) and the compound of formula (IIE-C-1)

R^(16A)—N═C═O  (IIE-C-1)

[0577] The reaction is carried out, for example, in an organic solvent(tetrahydrofuran, methylene chloride, diethyl ether, etc.) at atemperature of 0 to 100° C.

[0578] (2) A Method of Subjecting to a Reaction the Compound of Formula(IB) and the Compound of Formula (IIE-C-2)

[0579] in the presence of phosgene or 1,1-carbonyldiimidazole

[0580] This reaction is carried out, for example, in an organic solvent(tetrahydrofuran, methylene chloride, diethyl ether, dimethylformamide,etc.) at a temperature of 0 to 120° C.

[0581] (D) A Reaction to Form Urethane is Carried out According to theFollowing Method of (1) or (2).

[0582] (1) A Method of Subjecting to a Reaction the Compound of Formula(IB) and the Compound of Formula (IIE-D-1)

[0583] wherein all symbols have the same meanings as above.

[0584] This reaction is carried out, for example, in an organic solvent(tetrahydrofuran, methylene chloride, diethyl ether, etc.) at atemperature of −78 to 40° C.

[0585] (2) A Method of Subjecting to a Reaction the Compound of Formula(IB) and the Compound of Formula (IIE-D-2)

R^(16A)—OH  (IIE-D-2)

[0586] in the presence of N,N′-disuccinylcarbonate (DSC)

[0587] This reaction is carried out, for example, in an organic solvent(tetrahydrofuran, methylene chloride, diethyl ether, dimethylformamide,etc.) at a temperature of −78 to 120° C.

[0588] (E) N-Alkylation Reaction is Carried out by Subjecting to aReaction the Compound of Formula (IB) and the Compound of (IIE-E)

R^(X)—X^(B)  (IIE-E),

[0589] wherein R^(X) is C1-8 alkyl, Cyc, C1-8 alkyl substituted with Cycor nitro, or

[0590] N-alkylation is known, for example, it is carried out in an inertorganic solvent (dimethylformamide, dimethylsulfoxide, chloroform,methylene chloride, diethyl ether, tetrahydrofuran, acetonitrile, etc.)in the presence or absence of a base (triethylamine, pyridine, etc.) ata temperature of 0 to 100° C.

[0591] Furthermore, the compound of formula (ID) may also be preparedaccording to the method of 1) or 2).

[0592] 1) The compound of formula (ID) may be prepared by subjecting toamidation reaction the compound among the compounds of formula (IE),wherein R^(E) is hydrogen atom, AA^(1A) is a single bond, and none ofAA^(2E), R^(7E), R^(8E),

[0593] or R^(10E) contains carboxy, hydroxy, amino, thiol, guanidino,amidino or phosphono, i.e. the compound of formula (IE-1)

[0594] and the compound of formula (IIF)

R^(A)-AA^(1A)-OH  (IIF),

[0595] wherein all symbols have the same meanings as above.

[0596] 2) The compound of formula (ID) may also be prepared by thereactions of the compound among the compounds of formula (IE), whereinR^(E) is hydrogen, and none of AA^(1E), AA^(2E), R^(7E), R^(8E),

[0597] and R^(10E) contains carboxy, hydroxy, amino, thiol, guanidino,amidino or phosphono, i.e. the compound of formula (IE-2)

[0598] wherein all symbols have the same meanings as above, and thecompound of formula (IIE-A), (IIE-B), (IIE-C-1), (IIE-C-2), (IIE-D-1),(IIE-D-2) or (IIE-E).

[0599] That is, the compound of formula (ID) may also be prepared bysubjecting to

[0600] 2-A) an amidation reaction the compound of formula (IE-2) and thecompound of formula (IIE-A),

[0601] 2-B) a sulfonamidation reaction the compound of formula (IE-2)and the compound of formula (IIE-B),

[0602] 2-C) a reaction to form urea the compound of formula (IE-2) andthe compound of formula (IIE-C-1) or (IIE-C-2),

[0603] 2-D) a reaction to form urethane the compound of formula (IE-2)and the compound of formula (IIE-D-1) or (IIE-D-2), or

[0604] 2-E) an N-alkylation reaction the compound of formula (IE-2) andthe compound of formula (IIE-E).

[0605] Amidation, sulfonamidation, reactions to form urea and urethane,and N-alkylation may be carried out according to the methods describedabove.

[0606] The compounds of formula (IIA), (IIB), (IIC), (IID), (IIE-A),(IIE-B), (IIE-C), (IIE-D), (IIE-E) and (IIF) are known per se or may beprepared according to known methods.

[0607] For example, among the compound of formula (IIB), the compound offormula (IIB-1)

[0608] is known as CAS No. 4424-20-8 and the compound of formula (IIB-2)

[0609] may be prepared according to the following reaction scheme (1).

[0610] The compounds of formula (IIA) and (IID) may be preparedaccording to known methods, for example, the methods described in J.Med. Chem., 37, 563 (1994), EP 0623592-A, etc.

[0611] In each reaction of the present specification, reaction productsmay be purified by conventional techniques. For example, purificationmay be carried out by distillation under atmospheric or reducedpressure, by high performance liquid chromatography using silica gel ormagnesium silicate, by washing or by recrystallization, etc.Purification may be carried out after each reaction, or after a seriesof reactions. Other starting materials and agents used in the presentinvention are known per se or may be prepared by conventional methods.

[0612] Pharmacological Activity of the Compounds of the PresentInvention

[0613] The compound of formula (I) of the present invention has aninhibitory activity against cysteine proteases, and therefore it isuseful as an agent for the prophylaxis and/or treatment of inflammatorydiseases (periodontitis, arthritis, inflammatory bowel diseases,infectious diseases, pancreatitis, hepatitis, glomerulonephritis,endocarditis, myocarditis, etc.), diseases induced by apoptosis (graftversus host diseases, rejection of an organ transplantation, acquiredimmune deficiency syndrome (AIDS), AIDS-related complex (ARC), adult Tcell leukemia, hairy cells leukemia, spondylopathy, disorders ofrespiratory apparatus, arthritis, HIV or HTLV-1 related diseases such asuveitis, virus-related diseases such as hepatitis C, cancer,collagenosis (systemic lupus erythematosus, rheumatoid arthritis, etc.),ulcerative colitis, Sjoegren's syndrome, primary biliary cirrhosis,spontaneous thrombocytopenic purpura, autoimmune hemolytic anemia,myasthenia gravis, autoimmune diseases such as insulin dependent (typeI) diabetes, diseases accompanying thrombocytopenia (osteomyelodysplasiasyndrome, periodic thrombocytopenia, aplastic anemia, spontaneousthrombocytopenia, disseminated intravascular coagulation (DIC), etc.),hepatic diseases such as viral hepatitis (type A, B, C, F, etc.) orhepatitis medicamentosa and cirrhosis, dementia such as Alzheimer'sdiseases and Alzheimer's senile dementia, cerebrovascular injury, nervedegeneration diseases, adult acute respiratory distress syndrome,infectious diseases, prostatomegaly, hysteromyoma, bronchial asthma,arteriosclerosis, all kinds of lusus naturae, nephropathy, senilecataract, chronic fatigue syndrome, myodystrophy, peripheral neuropathy,etc.), diseases induced by disorders of immune response (graft versushost diseases, rejection of an organ transplantation, allergic diseases(bronchial asthma, atopic dermatitis, allergic rhinitis, pollinosis,diseases induced by house dusts, irritable pneumonia, food allergy,etc.), psoriasis, rheumatoid arthritis, etc.), auto immune diseases(insulin-dependent (type I) diabetes, systemic lupus erythematosus,Hashimoto's diseases, multiple sclerosis, etc.), desease by decomposingvarious proteins which compose the organism (myodystrophy, cataract,periodontitis, hepatocyte desease by bile acid such as cholestaticcirrhosis, etc.), decomposition of alveolus elastica such as pulmonaryemphysema, ischemic diseases (brain ischemia, brain disorders byischemic reperfusion, myocardial infarction, ischemic hepatopathy,etc.), shock (septic shock, systemic inflammation response syndrome,endotoxin shock, acidosis, etc.), circulatory system disorders(arteriosclerosis, restenosis after percutaneous transluminal coronaryangioplasty (PTCA), etc.)), blood coagulation disorders(thrombocytopenic purpura, hemolytic uremic syndrome, etc.), malignanttumor, acquired immune deficiency syndrome (AIDS) and AIDS-relatedcomplex (ARC), parasitic diseases such as malaria, nerve degenerativediseases (Alzheimer-type dementia, Huntington's chorea, Parkinson'sdiseases, multiple sclerosis, traumatic encephalopathy, traumaticspondylopathy, etc.), pulmopathy such as fibroid lungs, bone resorptiondiseases (osteoporosis, rheumatoid arthritis, arthritis, osteoarthritis,hypercalcemia, osteometastasis of cancer etc.), endocrinesthenia such ashyperthyroidism.

[0614] It was confirmed by the following experiments that the compoundsof the present invention of formula (I) have an inhibitory activityagainst cysteine protease.

[0615] (i) Measurement of Cathepsin K Inhibitory Activity

[0616] 65 μL of Cathepsin K enzyme reaction buffer (50 mmol/L of2-(N-morpholino)ethanesulfonate, 2 mmol/L of ethylenediaminetetraacetate (EDTA) and 4 mmol/L of dithiothreitol (DTT) were mixed toadjust to pH 5.5), 5 μL of cysteine protease inhibitor solution ofseveral concentrations, 20 μL of synthesized substrate(t-butyloxycarbonyl-L-alanyl-glycyl-L-prolyl-L-arginine-4-methyl-chromanyl-7-amide)solution of several concentrations and 10 μL of cathepsin K enzymesolution were mixed and the increase of fluorescence intensity whenreacted at 37° C. was measured (λ ex (excitation wavelength)=355 nm, λem (fluorescence wavelength)=460 nm). As to the substrate and thecompound of the present invention, enzyme reactions were carried out incombination of several appropriate concentrations and Dixon plotting wasprepared, to define the absolute value of X-coordinate of theintersection point of the graph as Ki value.

[0617] It was confirmed that the compound of the present invention offormula (I) had an inhibitory activity more than 50% at 10 μM. Forexample, the Ki values of inhibitory activity of the compounds ofexample 3, example 3 (14) and example 31 were 0.17 μM, 0.10 μM and 0.081μM respectively.

[0618] (ii) Measurement of Cathepsin B Inhibitory Activity

[0619] 10 μL of Synthesized substrate(carbobenzoxy-L-arginyl-L-arginine-4-methyl-chromanyl-7-amide orcarbobenzoxy-L-phenylalanyl-L-arginine-4-methyl-chromanyl-7-amide)solution of several concentrations, 10 μL of cysteine protease inhibitorsolution of several concentrations, 70 μL of cathepsin B enzyme reactionbuffer (mixture of 400 mmol/L in acetic acid, 4 mmol/L EDTA, 8 mmol/LDDT to adjust to pH 5.5) and 10 μL of cathepsin B enzyme solution weremixed and the increase of fluorescence intensity was measured (λ ex(excitation wavelength)=355 nm, μ em (fluorescence wavelength)=460 nm)when reacted at 37° C.

[0620] It was confirmed that the compound of the present invention offormula (I) had an inhibitory activity more than 50% at 10 μM. Forexample, the inhibitory activity of the compound of example 10 was 95%at 1 μM.

[0621] (iii) Measurement of Cathepsin S Inhibitory Activity

[0622] 10 μL of synthesized substrate(carbobenzoxy-L-leucyl-L-leucyl-L-arguinine-4-methyl-chromanyl-7-amide)solution and 5 μL of cysteine protease inhibitor solution of severalconcentrations, 75 μL of cathepsin S enzyme reaction buffer (100 mmol/Lof sodium phosphate, 2 mmol/L of EDTA, 2 mmol/L of DTT were mixed toadjust to pH 6.5) and 10 μL of cathepsin S enzyme solution were mixedand the increase of fluorescence intensity was measured (λ ex(excitationwavelength)=355 nm, λ em (fluorescence wavelength)=460 nm) when reactedat 37° C.

[0623] It was confirmed that the compound of the present invention offormula (I) has an inhibitory effect more than 50% at 10 μM. Forexample, the inhibitory activity of the compound of example 18 was 98%at 1 μM.

[0624] (iv) Measurement of Cathepsin L Inhibitory Activity

[0625] 5 μL of Synthesized substrate(carbobenzoxy-L-phenylalanyl-L-arguine-4-methyl-chromanyl-7-amide orL-prolyl-L-phenylalanyl-L-arguinine-4-methyl-chromanyl-7-amide) solutionand 5 μL of cysteine protease inhibitor solution of severalconcentrations, 80 μL of cathepsin L enzyme reaction buffer (400 mmol/Lacetic acid, 4 mmol/L EDTA, 8 mmol/L DTT were mixed to adjust to pH 5.5)and 10 μL of cathepsin L enzyme solution were mixed and the increase offluorescence intensity was measured (λ ex (excitation wavelength)=355nm, λ em (fluorescence wavelength)=460 nm) when reacted at 37° C.

[0626] It was confirmed that the compound of the present invention offormula (I) had an inhibitory activity of more than 50% at 10 μM. Forexample, the inhibitory activity of the compound of example 22(4) was97% at 1 μM.

[0627] (v) Measurement of Calpain Inhibitory Activity

[0628] The activity was measured according to the method described inCalcium-depending protease, Seibutsukagaku-Jikkenhou (BiochemistryExperimental Method) Tanpakubunkaikouso (Protease) I, 57 (1993).

[0629] (vi) Measurement of Caspase-1 Inhibitory Activity

[0630] 50 μL of caspase-1 enzyme reaction solution (20 mmol/L of4-(2-hydroxyethyl)-1-piperazinethanesulfonate-sodium hydroxide buffer pH7.4, 10 mmol/L of potassium chloride, 1.5 mmol/L of magnesium chloride,0.1 mmol/L EDTA, 10% glycerol) and 50 μL of cysteine protease inhibitorsolution of several concentrations, 50 μL of caspase-1 enzyme solutionand 100 μL of synthesized substrate(acetyl-L-tyrosinyl-L-valinyl-L-alanyl-L-asparticacid-4-methyl-chromanyl-7-amide) solution of several concentrations werereacted at 37° C. and the fluorescence intensity was measured (λ ex(excitation wavelength)=355 nm, λ em (fluorescence wavelength)=460 nm).

[0631] (vii) Investigation in Bone Resorption Inhibitory Activity UsingMouse Calvaria Cultivation System

[0632] Mouse neonatal calvaria was cultured in D-minimal essentialmedium containing cysteine protease inhibitor (mixture of Penicillin Gpotassium (final concentration 100 U/ml), streptomycin sulfate (finalconcentration 0.1 mg/ml), bovine serum albumin (final concentration0.1%), glutamine (final concentration 0.3 mg/ml) in D-minimal essentialmedium) at 37° C. and the calcium concentration in the culture mediumwas measured.

[0633] (viii) Bone Resorption Pit Formation Test Using Rabbit OsteoclastCells

[0634] Osteoclast cells collected from rabbit bones were sowed overslices of bovine cortical bone, ivory or teeth of toothed whale and werecultured at 37° C. in α-minimal essential medium containing finalconcentration 5% of fetal bovine serum and various concentrations ofcysteine protease inhibitor. The pits formed on the slices by theosteoclast cells were observed and at the same time type-I collagenC-terminal telopeptide (CTx) concentration in culture medium wasmeasured.

[0635] (ix) Investigation of Immune Reaction Inhibitory Effect UsingAntigen-Sensitized Mouse Spleen Cells

[0636] Spleen cells were collected from mice sensitized by ovalbumin(OVA) several times. Inhibitory effect of cysteine protease inhibitorsagainst immune response induced by OVA stimulus was investigated, usingcytokine concentration and immunoglobulin concentration in culturesolution as indicators.

[0637] (x) Investigation in Inhibitory Effect Against Bone ResorptionUsing the Rat PTH Hypercalcemia Model

[0638] The effect of cysteine protease inhibitor (compulsory oraladministration, intraperitoneal administration) on bone resorption whichwas promoted by intravenous administration of parathyroid hormone (PTH)solution (30 μg/ml) was investigated in rats, using calciumconcentration in blood as an indicator.

[0639] (xi) Studies on Bone Resorption Inhibitory Effect Using TPTx RatPTHrP-Induced Hypercalcemia Model

[0640] The effect of cysteine protease inhibitor (compulsory oraladministration, intraperitoneal administration) on bone resorption,promoted by subcutaneous administration of parathyroid hormone relatedpeptide (PTHrP) to a fasting rat (thyroparathyroidectomized; TPTx) wasinvestigated, using calcium concentration in blood as an indicator.

[0641] Toxicity

[0642] The toxicity of the compounds of the present invention is verylow and therefore it was confirmed that the compounds are safe forpharmaceutical use.

INDUSTRIAL APPLICABILITY

[0643] Application to Pharmaceuticals

[0644] The compound of formula (I) of the present invention has aninhibitory activity against cysteine proteases, and therefore it isuseful as an agent for the prophylaxis and/or treatment of inflammatorydiseases (periodontitis, arthritis, inflammatory bowel diseases,infectious diseases, pancreatitis, hepatitis, glomerulonephritis,endocarditis, myocarditis, etc.), diseases induced by apoptosis (graftversus host diseases, rejection of an organ transplantation, acquiredimmune deficiency syndrome (AIDS), AIDS-related complex (ARC), adult Tcell leukemia, hairy cells leukemia, spondylopathy, disorders ofrespiratory apparatus, arthritis, HIV or HTLV-1 related diseases such asuveitis, virus-related diseases such as hepatitis C, cancer,collagenosis (systemic lupus erythematosus, rheumatoid arthritis, etc.),ulcerative colitis, Sjoegren's syndrome, primary biliary cirrhosis,spontaneous thrombocytopenic purpura, autoimmune hemolytic anemia,myasthenia gravis, autoimmune diseases such as insulin dependent (typeI) diabetes, diseases accompanying thrombocytopenia (osteomyelodysplasiasyndrome, periodic thrombocytopenia, aplastic anemia, spontaneousthrombocytopenia, disseminated intravascular coagulation (DIC), etc.),hepatic diseases such as viral hepatitis (type A, B, C, F, etc.) orhepatitis medicamentosa and cirrhosis, dementia such as Alzheimer'sdiseases and Alzheimer's senile dementia, cerebrovascular injury, nervedegeneration diseases, adult acute respiratory distress syndrome,infectious diseases, prostatomegaly, hysteromyoma, bronchial asthma,arteriosclerosis, all kinds of lusus naturae, nephropathy, senilecataract, chronic fatigue syndrome, myodystrophy, peripheral neuropathy,etc.), diseases induced by disorders of immune response (graft versushost diseases, rejection of an organ transplantation, allergic diseases(bronchial asthma, atopic dermatitis, allergic rhinitis, pollinosis,diseases induced by house dusts, irritable pneumonia, food allergy,etc.), psoriasis, rheumatoid arthritis, etc.), autoimmune diseases(insulin-dependent (type I) diabetes, systemic lupus erythematosus,Hashimoto's diseases, multiple sclerosis, etc.), desease by decomposingvarious proteins which compose the organism (myodystrophy, cataract,periodontitis, hepatocyte desease by bile acid such as cholestaticcirrhosis, etc.), decomposition of alveolus elastica such as pulmonaryemphysema, ischemic diseases (brain ischemia, brain disorders byischemic reperfusion, myocardial infarction, ischemic hepatopathy,etc.), shock (septic shock, systemic inflammation response syndrome,endotoxin shock, acidosis, etc.), circulatory system disorders(arteriosclerosis, restenosis after percutaneous transluminal coronaryangioplasty (PTCA), etc.)), blood coagulation disorders(thrombocytopenic purpura, hemolytic uremic syndrome, etc.), malignanttumor, acquired immune deficiency syndrome (AIDS) and AIDS-relatedcomplex (ARC), parasitic diseases such as malaria, nerve degenerativediseases (Alzheimer-type dementia, Huntington's chorea, Parkinson'sdiseases, multiple sclerosis, traumatic encephalopathy, traumaticspondylopathy, etc.), pulmopathy such as fibroid lungs, bone resorptiondiseases (osteoporosis, rheumatoid arthritis, arthritis, osteoarthritis,hypercalcemia, osteometastasis of cancer etc.), endocrinesthenia such ashyperthyroidism.

[0645] For the purpose described above, the compounds of formula (I), ofthe present invention, non-toxic salts thereof, acid addition saltsthereof or hydrates thereof may normally be administered systemically orlocally, usually by oral or parenteral administration.

[0646] The doses to be administered are determined depending upon, forexample, age, body weight, symptom, the desired therapeutic effect, theroute of administration, and the duration of the treatment. In the humanadult, the doses per person at a time are generally from 1 mg to 1000mg, by oral administration, up to several times per day, and from 1 mgto 100 mg, by parenteral administration (preferably intravenousadministration), up to several times per day, or continuousadministration for from 1 to 24 hours per day from vein.

[0647] As mentioned above, the doses to be used depend upon variousconditions. Therefore, there are cases wherein doses lower than orgreater than the ranges specified above may be used.

[0648] The compounds of the present invention may be administered in theform of, for example, solid compositions, liquid compositions or othercompositions for oral administration, injections, liniments orsuppositories for parenteral administration.

[0649] Solid compositions for oral administration include compressedtablets, pills, capsules, dispersible powders and granules.

[0650] Capsules include hard capsules and soft capsules.

[0651] In such solid compositions, one or more of the active compound(s)may be used as a dosage form, as is normal practice, to admix withexcipient (e.g. lactose, mannitol, glucose, microcrystalline cellulose,starch), combining agents (hydroxypropyl cellulose, polyvinylpyrrolidone or magnesium metasilicate aluminate), disintegrating agents(e.g. cellulose calcium glycolate), lubricating agents (e.g. magnesiumstearate), stabilizing agents, agents to assist dissolution (e.g.glutamic acid or asparatic acid)and the like. The agents may, ifdesired, be coated with coating agents (e.g. sugar, gelatin,hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), orbe coated with two or more films. Further, coating may includecontainment within capsules of absorbable materials such as gelatin.

[0652] Liquid compositions for oral administration includepharmaceutically acceptable solutions, suspensions, emulsions, syrupsand elixirs. In such compositions, one or more of the active compound(s)are dissolved, suspended or emulsified in diluent commonly used (e.g.purified water, ethanol or mixture thereof). Furthermore, such liquidcompositions may also comprise wetting agents or suspending agents,emulsifying agents, sweetening agents, flavouring agents, perfumingagents, preserving agents buffer agent etc.

[0653] Injections for parenteral administration include solutions,suspensions, emulsions and solids which are dissolved or suspended touse at a time to use. One or more of the active compound(s) ininjections are dissolved, suspended and emulsified in a solvent. Thesolvents are, for example, distilled water for injection, physiologicalsalt solution, vegetable oil, propylene glycol, polyethylene glycol,alcohol such as ethanol or mixture thereof. Moreover the injections mayalso include stabilizing agents, agents to assist dissolution (e.g.glutamic acid, aspartic acid or POLYSORBATE80 (registered trade mark)),suspending agents, emulsifying agents, soothing agents, buffer agents,preserving agents, etc. They are sterilized in the last process ormanufactured and prepared by sterile procedure. They may also bemanufactured in the form of sterile solid compositions such asfreeze-dried one and they may be sterilized or dissolved to use insterile distilled water for injection or some other solvents immediatelybefore use.

[0654] Other compositions for parenteral administration include liquidsfor external use, and ointment, endermic liniments, inhale, spray,suppositories for rectal administration and pessaries for vaginaladministration which comprise one or more of the active compound(s) andare prescribed by methods known per se.

[0655] Spray compositions may comprise additional substances other thandiluents: e.g. stabilizing agents (e.g. sodium sulfitehydride), isotonicbuffers (e.g. sodium chloride, sodium citrate or citric acid). Forpreparation of such spray compositions, for example, the methoddescribed in the U.S. Pat. No. 2,868,691 or No. 3,095,355 may be used.

BEST MODE FOR CARRYING OUT THE INVENTION

[0656] The following reference examples and examples illustrate thepresent invention, but do not limit the present invention.

[0657] The solvents in the parentheses show the eluting or developingsolvents and the ratios of the solvents used are by volume inchromatographic separations or TLC.

[0658] The solvents in the parentheses in NMR show the solvents used inmeasurement.

REFERENCE EXAMPLE 1

[0659] (3S)-1-bromo-3-(t-butoxycarbonylamino)-5-methyl-2-hexanone

[0660] Under atmosphere of argon, to a solution of(2S)-2-(t-butoxycarbonylamino)-4-methylpentanoic acid(t-butoxycarbonyl-L-leucine) (37.4 g) in tetrahydrofuran (800 ml) wasadded N-methylmorpholine (33 ml) at −25° C. and the mixture was stirredfor 10 minutes. To the mixture was added chloroethylformate (15.8 ml)and the mixture was stirred for 20 minutes. Thereto was added a solutionof diazomethane in diethyl ether and the mixture was stirred for another2 hours. Thereto was added a mixture of 47% hydrobromic acid-acetic acid(1:1) at 0° C. and the mixture was stirred for 15 minutes. To thereaction mixture was added water and was extracted with a mixture ofethyl acetate-hexane. The organic layer was washed with a saturatedaqueous solution of sodium bicarbonate and a saturated aqueous solutionof sodium chloride successively, dried over anhydrous sodium sulfate andwas concentrated. The residue was washed with cooled hexane to give thetitle compound (27.4 g) having the following physical data.

[0661] TLC: Rf 0.56 (n-hexane:ethyl acetate=3:1);

[0662] NMR (CDCl₃): δ 4.89 (m, 1H), 4.53 (m, 1H), 4.08 (m, 2H),1.80-1.31 (m, 12H), 0.97 (m, 6H)

EXAMPLE 1

[0663](3S)-3-(t-butoxycarbonylamino)-5-methyl-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-2-hexanone

[0664] To a solution of 1,3,4,5-tetrahydro-2H-2-benzazepin(2.2 g) indimethylformamide (30 ml) was added the compound prepared in referenceexample 1 (4.1 g) and the mixture was stirred for 1.5 hours. To thereaction mixture was added diisopropylethylamine (2.3 ml) and themixture was stirred for another 3.5 hours. To the reaction mixture wasadded ice-water and was extracted with ethyl acetate. The organic layerwas washed with a saturated aqueous solution of sodium bicarbonate,water and a saturated aqueous solution of sodium chloride successively,dried over anhydrous sodium sulfate and was concentrated. The residuewas purified by column chromatography on silica gel (n-hexane:ethylacetate=5:1-3:1-1:1) to give the compound of the present invention (4.7g) having the following physical data.

[0665] TLC: Rf 0.48 (n-hexane:ethyl acetate=6:4);

[0666] NMR (CDCl₃): δ 7.20-7.00 (m, 4H), 4.97 (d, J=8.4 Hz, 1H),4.40-4.30 (m, 1H), 3.98 (s, 2H), 3.33 (d, J=18.2 Hz, 1H), 3.30 (d,J=18.2 Hz, 1H), 3.17 (t, J=5.3 Hz, 2H), 2.95-2.85 (m, 2H), 1.80-1.70 (m,2H), 1.42 (s, 9H), 1.50-1.20 (m, 3H), 0.892 (d, J=6.6 Hz, 3H), 0.887 (d,J=6.3 Hz, 3H).

EXAMPLE 2

[0667](3S)-3-amino-5-methyl-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-2-hexanonedihydrochloride

[0668] To a solution of the compound prepared in example 1 (187 mg) inmethanol (1 ml) was added 4N hydrochloric acid in ethyl acetate (4 ml)at 0° C. and the mixture was stirred for 1 hour. The reaction mixturewas concentrated to give a crude product of the present invention havingthe following physical data. The crude product was used in the nextreaction without further purification.

[0669] TLC: Rf 0.71 (chloroform:methanol:28% ammonia water=8:2:0.4);

[0670] NMR (CD₃OD): δ 7.50-7.05 (m, 4H), 5.02-4.90 (m, 3H), 4.60-4.30(m, 2H), 3.75-3.60 (m, 2H) 3.20-3.00 (m, 2H); 2.20-2.00 (m, 2H),1.90-1.60 (m, 3H), 1.12-0.90 (m, 6H).

EXAMPLE 3

[0671]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-benzamidecyclohexyl]carboxamide

[0672] To a solution of (−)-2-benzamidocyclohexanecarboxylic acid((1R,2S)-2-benzamidocyclohexanecarboxylic acid) (148 mg) and1-hydroxybenzotriazole (107 mg) in dimethylformamide (2 ml) was added1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (134 mg)and the mixture was stirred for 30 minutes, and thereto was added thecompound prepared in example 2 and triethylamine (140 ml) and wasstirred for another 2 hours. To the reaction mixture was added ice-waterand was extracted with ethyl acetate. The organic layer was washed witha saturated aqueous solution of sodium bicarbonate, water and asaturated aqueous solution of sodium chloride successively, dried overanhydrous sodium sulfate and was concentrated. The residue was purifiedby column chromatography on silica gel (chloroform:methanol=1:0-100:1)to give the compound of the present invention as a free compound (225mg). It was converted into its hydrochloride by a known method to givethe hydrochloride having the following physical data.

[0673] [Free Compound]

[0674] TLC: Rf 0.48 (chloroform:methanol=9:1);

[0675] NMR (CDCl₃): δ 7.85-7.70 (m, 2H), 7.60-6.95 (m, 8H), 6.12 (d,J=8.7 Hz, 1H), 4.75-4.60 (m, 1H), 4.35-4.25 (m, 1H), 3.98 and 3.94 (eachs, totally 2H), 3.35-3.25 (m, 2H), 3.20-3.05 (m, 2H), 2.95-2.85 (m, 2H),2.80-2.70 (m, 1H), 2.20-1.20 (m, 13H), 0.90-0.65 (m, 6H).

[0676] [Hydrochloride]

[0677] TLC: Rf 0.64 (chloroform:methanol=9:1);

[0678] NMR (CDCl₃): δ 8.19 and 7.60 (each br, total 1H), 7.86-7.66 (m,2H), 7.53-7.01 (m, 8H), 4.60-4.22 (m, 5H), 3.77-3.45 (m, 3H), 3.04-2.78(m, 3H), 2.19-1.26 (m, 13H), 0.98-0.62 (m, 6H)

EXAMPLE 3(1)-EXAMPLE 3(24)

[0679] By the same procedure as described in example 3 using acarboxylic acid corresponding to(1R,2S)-2-benzamidocyclohexanecarboxylic acid and the compound preparedin example 2 or a corresponding amine, the compound of the presentinvention having the following physical data was obtained.

EXAMPLE 3(1)

[0680]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-cyclohexylcarboxamide

[0681] TLC: Rf 0.55 (chloroform:methanol=9:1);

[0682] NMR (CDCl₃): δ 7.20-7.00 (m, 4H), 5.90 (d, J=8.0 Hz, 1H),4.80-4.65 (m, 1H), 3.98 (s, 2H), 3.33 (s, 2H), 3.25-3.10 (m, 2H),2.95-2.80 (m, 2H), 2.20-2.00 (m, 1H), 2.00-1.10 (m, 15H), 0.88 (d, J=6.4Hz, 3H), 0.88 (d, J=6.2 Hz, 3H).

EXAMPLE 3(2)

[0683]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1S,2R)-2-benzoylaminocyclohexyl]carboxamide

[0684] TLC: Rf 0.48 (chloroform:methanol=9:1);

[0685] NMR (CDCl₃): δ 7.90-7.70 (m, 2H), 7.57 (d, J=8.4 Hz, 1H),7.50-7.35 (m, 3H), 7.20-6.95 (m, 4H), 6.08 (d, J=7.8 Hz, 1H), 4.80-4.65(m, 1H), 4.35-4.20 (m, 1H), 3.97 and 3.93 (each s, totally 2H),3.35-3.20 (m, 2H), 3.20-3.05 (m, 2H), 2.95-2.85 (m, 2H), 2.80-2.70 (m,1H), 2.10-1.20 (m, 13H), 0.87, 0.75 and 0.74 (each d, J=6.3 Hz, totally6H).

EXAMPLE 3(3)

[0686]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide

[0687] TLC: Rf 0.57 (chloroform:methanol=9:1);

[0688] NMR (CDCl₃): δ 7.85-7.75 (m, 2H), 7.55-7.40 (m, 3H), 7.20-7.00(m, 4H), 6.72 (d, J=8.1 Hz, 1H), 5.05-4.95 (m, 1H), 3.99 (each s,totally 2H), 3.39 (d, J=17.7 Hz, 1H), 3.36 (d, J=17.7 Hz, 1H), 3.25-3.10(m, 2H), 2.95-2.85 (m, 2H), 1.80-1.40 (m, 5H), 0.95 (d, J=6.3 Hz, 3H),0.92 (d, J=6.3 Hz, 3H).

EXAMPLE 3(4)

[0689]4-benzyloxy-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide

[0690] TLC: Rf 0.28 (n-hexane:ethyl acetate=1:1);

[0691] NMR (CDCl₃): δ 7.75 (d, J=8.8 Hz, 2H), 7.50-7.30 (m, 5H),7.20-6.90 (m, 6H), 6.65 (d, J=8.8 Hz, 1H), 5.12 (s, 2H), 4.96 (dt,J=8.8, 3.8 Hz, 1H), 3.99 (s, 2H), 3.40 (d, J=17.6 Hz, 1H), 3.36 (d,J=17.6 Hz, 1H), 3.25-3.10 (m, 2H), 2.95-2.85 (m, 2H), 1.90-1.20 (m, 5H),0.93 (d, J=6.0 Hz, 3H), 0.91 (d, J=6.2 Hz, 3H).

EXAMPLE 3(5)

[0692]3-benzyloxy-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide

[0693] TLC: Rf 0.36 (n-hexane:ethyl acetate=1:1);

[0694] NMR (CDCl₃): δ 7.50-7.30 (m, 8H), 7.20-7.00 (m, 5H), 6.70 (d,J=8.4 Hz, 1H), 5.11 (s, 2H), 4.96 (dt, J=8.4, 4.0 Hz, 1H), 3.99 (s, 2H),3.37 (s, 2H), 3.25-3.10 (m, 2H), 2.95-2.85 (m, 2H), 1.80-1.20 (m, 5H),0.94 (d, J=6.4 Hz, 3H), 0.92 (d, J=6.2 Hz, 3H).

EXAMPLE 3(6)

[0695]2-benzyloxy-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide

[0696] TLC: Rf 0.31 (n-hexane:ethyl acetate=1:1);

[0697] NMR (CDCl₃): δ 8.30-8.10 (m, 2H), 7.55-7.35 (m, 6H), 7.20-6.95(m, 6H), 5.18 (d, J=10.6 Hz, 1H), 5.14 (d, J=10.6 Hz, 1H), 4.80-4.70 (m,1H), 3.95 (s, 2H), 3.37 (d, J=17.8 Hz, 1H), 3.31 (d, J=17.8 Hz, 1H),3.20-3.10 (m, 2H), 2.95-2.80 (m, 2H), 1.80-1.00 (m, 5H), 0.75 (d, J=6.0Hz, 3H), 0.66 (d, J=6.2 Hz, 3H).

EXAMPLE 3(7)

[0698]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]cinnamide

[0699] TLC: Rf 0.27 (n-hexane:ethyl acetate=1:1);

[0700] NMR (CDCl₃): δ 7.62 (d, J=15.6 Hz, 1H), 7.55-7.45 (m, 2H),7.40-7.30 (m, 3H), 7.20-7.00 (m, 4H), 6.41 (d, J=15.6 Hz, 1H), 6.19 (d,J=8.6 Hz, 1H), 4.94 (dt, J=8.6, 4.4 Hz, 1H), 3.99 (s, 2H),3.56 (s, 2H),3.25-3.10 (m, 2H), 2.95-2.85 (m, 2H), 1.80-1.20 (m, 5H), 0.93 (d, J=6.0Hz, 3H), 0.91 (d, J=6.2 Hz, 3H).

EXAMPLE 3(8)

[0701]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-3-cyclopentylpropanamide

[0702] TLC: Rf 0.30 (n-hexane:ethyl acetate=1:1);

[0703] NMR (CDCl₃): δ 7.20-7.03 (m, 4H), 6.08 (d, J=8.1 Hz, 1H), 4.71(m, 1H), 4.04 (s, 2H), 3.46 (d, J=18.0 Hz, 1H), 3.35 (d, J=18.0 Hz, 1H),3.23 (m, 2H), 2.92 (m, 2H), 2.21 (t, J=7.5 Hz, 2H), 1.80-1.20 and1.18-1.00 (totally 16H), 0.89 (d, J=6.6 Hz, 3H), 0.88 (d, J=6.6 Hz, 3H).

EXAMPLE 3(9)

[0704]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-2-(5-phenylimidazolidin-2,4-dion-3-yl)acetamide

[0705] TLC: Rf 0.41 (chloroform:methanol=9:1);

[0706] NMR (CDCl₃): δ 7.50-7.29 (m, 5H), 7.22-6.98 (m, 4H), 6.74-6.51(m, 1H), 6.31, 6.19, 6.14 and 6.11 (each brs, totally 1H), 5.15 (s, 1H),4.78-4.64 (m, 1H), 4.28-4.11 (m, 2H), 3.95and 3.94 (each s, totally 2H),3.43-3.19 (m, 2H), 3.19-3.05 (m, 2H), 2.94-2.83 (m, 2H), 1.80-1.20 (m,5H), 1.00-0.77 (m, 6H).

EXAMPLE 3(10)

[0707]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-2-(2-phenyl-1,6-dihydropyrimidin-6-on-1-yl)acetamide

[0708] TLC: Rf 0.47 (chloroform:methanol=9:1);

[0709] NMR (CDCl₃): δ 8.00 (d, J=6.5 Hz, 1H), 7.65-7.40 (m, 5H),7.23-7.00 (m, 4H), 6.51 (d, J=8.0 Hz, 1H), 6.50 (d, J=6.5 Hz, 1H), 4.74(ddd, J=12.0, 8.0 and 4.2 Hz, 1H), 4.57 (d, J=15.3 Hz, 1H), 4.46 (d,J=15.3 Hz, 1H), 3.97 (s, 2H), 3.38 (d, J=17.4 Hz, 1H), 3.28 (d, J=17.4Hz, 1H), 3.22-3.09 (m, 2H), 2.97-2.84 (m, 2H), 1.83-1.20 (m, 5H), 0.87(d, J=6.3 Hz, 6H).

EXAMPLE 3(11)

[0710]2-benzoylamino-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide

[0711] TLC: Rf 0.32 (hexane:ethyl acetate=6:4);

[0712] NMR (CDCl₃): δ 12.07 (s, 1H), 8.85 (d, J=8.4 Hz, 1H), 8.02 (dd,J=7.6, 2.2 Hz, 2H), 7.65-7.40 (m, 5H), 7.20-7.00 (m, 5H), 6.97 (d, J=8.8Hz, 1H), 5.01 (dt, J=3.6, 8.8 Hz, 1H), 4.00 (s, 2H), 3.42 (d, J=17.4 Hz,1H), 3.36 (d, J=17.4 Hz, 1H), 3.25-3.10 (m, 2H), 3.00-2.85 (m, 2H),2.00-1.60 (m, 5H), 0.95 (d, J=5.8 Hz, 3H), 0.93 (d, J=5.8 Hz, 3H).

EXAMPLE 3(12)

[0713](3S)-5-methyl-3-(2-methylpropoxycarbonylamino)-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)hexan-2-one

[0714] TLC: Rf 0.45 (hexane:ethyl acetate=6:4);

[0715] NMR (CDCl₃): δ 7.20-7.00 (m, 4H), 5.16 (d, J=8.4 Hz, 1H),4.55-4.35 (m, 1H), 3.97 (s, 2H), 3.83 (d, J=6.6 Hz, 2H), 3.31 (s, 2H),3.25-3.10 (m, 2H), 2.95-2.85 (m, 2H), 2.00-1.20 (m, 6H), 1.00-0.80 (m,12H).

EXAMPLE 3(13)

[0716](2S)-N-[5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[1-phenethylpiperidin-2-yl]carboxamide

[0717] TLC: Rf 0.54 (chloroform:methanol=9:1);

[0718] NMR (CDCl₃): δ 7.35-7.00 (m, 9H), 6.94 and 6.70 (each d, J=8.4and 7.6 Hz, totally 1H), 4.65-4.45 (m, 1H), 3.97 (s, 2H), 3.40-3.10 (m,5H), 3.10-2.65 (m, 6H), 2.60-1.00 (m, 13H), 1.00-0.70 (m, 6H).

EXAMPLE 3(14)

[0719](2S)-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

[0720] TLC: Rf 0.45 (n-hexane:ethyl acetate=1:1);

[0721] NMR (CDCl₃): δ 7.40-7.00 (m, 9H), 6.35 (d, J=7.5 Hz, 1H), 5.13(d, J=9.3 Hz, 1H), 5.10 (s, 2H), 4.70 (m, 1H), 4.15 (m, 1H), 3.97 (s,2H), 3.30 (s, 2H), 3.16 (m, 2H), 2.90 (m, 2H), 1.80-1.20 (m, 8H), 0.93(m, 6H), 0.86 (m, 6H)

EXAMPLE 3(15)

[0722](2S)-N-[5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

[0723] TLC: Rf 0.45 (methanol:ethyl acetate=19:1);

[0724] NMR (CDCl₃): δ 7.40-7.00 (m, 9H), 6.57 and 6.38 (each brd, J=7.8Hz, totally 1H), 5.20-5.12 (m, 3H), 4.69 (m, 1H), 4.20 (m, 1H), 3.99 and3.97 (each s, totally 2H), 3.30 (m, 2H), 3.17 (m, 2H), 2.91 (m, 2H),1.80-1.30 (m, 8H), 1.00-0.80 (m, 12H).

EXAMPLE 3(16)

[0725](2S)-N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

[0726] TLC: Rf 0.42 (hexane:ethyl acetate=1:1);

[0727] NMR (CDCl₃): δ 7.49-6.95 (m, 9H), 6.70 and 6.50 (each d, J=7.2and 6.0 Hz, totally 1H), 5.30-4.96 (m, 3H), 4.74-4.58 (m, 1H), 4.30-4.06(m, 1H), 4.01 (s, 2H), 3.50-3.03 (m, 4H), 3.03-2.80 (m, 2H), 2.11-1.20(m, 8H), 1.07-0.74 (m, 12H).

EXAMPLE 3(17)

[0728](2R)-N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

[0729] TLC: Rf 0.42 (hexane:ethyl acetate=1:1);

[0730] NMR (CDCl₃): δ 7.51-6.96 (m, 9H), 6.60 and 6.46 (each d, J=8.4Hz, totally 1H), 5.30-4.92 (m, 3H), 4.77-4.60 (m, 1H), 4.30-4.06 (m,1H), 3.99 (s, 2H), 3.46-3.04 (m, 4H), 3.04-2.77 (m, 2H), 2.05-1.20 (m,8H), 1.07-0.74 (m, 12H).

EXAMPLE 3(18)

[0731]1-cyclohexyl-N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]carboxamide

[0732] TLC: Rf 0.31 (hexane:ethyl acetate=1:1);

[0733] NMR (CDCl₃): δ 7.24-7.00 (m, 4H), 5.95 (d, J=8.1 Hz, 1H), 4.70(ddd, J=9.8, 8.1, 3.9 Hz, 1H), 4.01 (s, 2H), 3.40 (d, J=18.0 Hz, 1H),3.32 (d, J=18.0 Hz, 1H), 3.25-3.14 (m, 2H), 2.97-2.86 (m, 2H)),2.19-2.00(m, 1H), 1.95-1.06 (m, 15H), 0.89 (d, J=6.5 Hz, 3H), 0.88 (d, J=6.5 Hz,3H).

EXAMPLE 3(19)

[0734]N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-3-cyclopentylpropanamide

[0735] TLC: Rf 0.32 (hexane:ethyl acetate=1:1);

[0736] NMR (CDCl₃): δ 7.23-7.00 (m, 4H), 5.95 (d, J=8.4 Hz, 1H), 4.74(ddd, J=9.8, 8.4, 4.2 Hz, 1H), 4.00 (s, 2H), 3.39 (d, J=18.0 Hz, 1H),3.31 (d, J=18.0 Hz, 1H), 3.23-3.14 (m, 2H), 2.95-2.86 (m, 2H), 2.29-2.14(m, 2H), 1.96-1.20 and 1.20-0.96 (each m, totally 13H), 0.89 (d, J=6.6Hz, 3H), 0.88 (d, J=6.6 Hz, 3H).

EXAMPLE 3(20)

[0737]N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

[0738] TLC: Rf 0.52 (chloroform:methanol=9:1);

[0739] NMR (CDCl₃): δ 7.90-7.70 (m, 2H), 7.60-7.33 (m, 4H), 7.22-6.95(m, 4H), 6.24 and 6.17 (each d, J=8.1 Hz, totally 1H), 4.76-4.57 (m,1H), 4.40-4.19 (m, 1H), 3.98 and 3.97 (each s, totally 2H), 3.44-3.22(m, 2H), 3.22-3.02 (m, 2H), 2.96-2.80 (m, 2H), 2.80-2.66 (m, 1H),2.16-1.15 (m, 13H), 0.86, 0.75 and 0.74 (each d, J=6.5 Hz, totally 6H).

EXAMPLE 3(21)

[0740]N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1S,2R)-2-benzoylaminocyclohexyl]carboxamide

[0741] TLC: Rf 0.52 (chloroform:methanol=9:1);

[0742] NMR (CDCl₃): δ 7.90-7.70 (m, 2H), 7.57-7.31 (m, 4H), 7.21-6.96(m, 4H), 6.34 and 6.20 (each d, J=8.7 Hz, totally 1H), 4.78-4.60 (m,1H), 4.41-4.16 (m, 1H), 4.00 (s, 2H), 3.48-3.24 (m, 2H), 3.24-3.07 (m,2H), 2.98-2.81 (m, 2H), 2.81-2.68 (m, 1H), 2.20-1.20 (m, 13H), 0.87,0.75 and 0.74 (each d, J=6.6 Hz, totally 6H).

EXAMPLE 3(22)

[0743] (2S)-N-[1-(2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)acetyl)cyclohexan-1-yl]-4-methyl-2-benzyloxycarbonylamino pentanamide

[0744] TLC: Rf 0.39 (chloroform:methanol=9:1);

[0745] NMR (CDCl₃): δ 7.34 (s, 5H), 7.17-7.00 (m, 4H), 6.39 (brs, 1H),5.12 (d, J=12.3 Hz, 1H), 5.06 (d, J=12.3 Hz, 1H), 5.00 (m, 1H), 4.08 (m,1H), 3.96 (s, 2H), 3.40 (s, 2H), 3.13 (t, J=5.4 Hz, 2H), 2.87 (m, 2H),1.90 (m, 2H), 1.80-1.10 (m, 13H), 1.00-0.84 (m, 6H).

EXAMPLE 3(23)

[0746] (2S)-N-[1-(2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)acetyl)cyclohexan-1-yl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

[0747] TLC: Rf 0.41 (ethyl acetate);

[0748] NMR (CDCl₃): δ 7.81 (m, 2H), 7.60-6.93 (m, 8H), 5.83 (brs, 1H),4.30 (m, 1H), 3.93 (d, J=14.7 Hz, 1H), 3.88 (d, J=14.7 Hz, 1H), 3.40 (m,2H), 3 20-2.78 (m, 5H), 2.10-1.10 (m, 20H)

EXAMPLE 3(24)

[0749]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-2-(1,3-diazaspiro[4,5]decane-2,4-dion-3-yl)acetamide

[0750] TLC: Rf 0.32 (chloroform:methanol=9:1);

[0751] NMR (CDCl₃): δ 7.25-7.00 (m, 4H), 6.76 and 6.66 (each d, J=8.0Hz, totally 1H), 6.40 and 6.26 (each brs, totally 1H), 4.80-4.64 (m,1H), 4.25-4.04 (m, 2H), 3.98 (s, 2H), 3.38 (d, J=17.7 Hz, 1H), 3.29 (d,J=17.7 Hz, 1H), 3.24-3.10 (m, 2H), 2.97-2.83 (m, 2H), 2.03-1.20 (m,15H), 0.88 (d, J=6.3 Hz, 3H), 0.87 (d, J=6.3 Hz, 3H).

REFERENCE EXAMPLE 2

[0752] (1R,2S)-2-(t-butoxycarbonylamino)cyclohexylmethylalcohol

[0753] To a solution of (1R,2S)-2-aminocyclohexylmethylalcohol (500 mg)in tetrahydrofuran (25 ml) was added di-t-butyl-dicarbonate (0.98 ml)and the mixture was stirred for 1 hour at room temperature. The reactionmixture was concentrated and the residue was dried under reducedpressure to give the title compound (1.18 g) having the followingphysical data.

[0754] TLC: Rf 0.32 (n-hexane:ethyl acetate=3:1);

[0755] NMR (CD₃OD): δ 3.92-3.80 (br, 1H), 3.48-3.26 (m, 2H), 1.80-1.10(m, 9H), 1.44 (s, 9H).

REFERENCE EXAMPLE 3

[0756] (1R,2S)-2-(t-butoxycarbonylamino)cyclohexanecarbaldehyde

[0757] Under atmosphere of argon, to a solution of the compound preparedin reference example 2 (1.18 g) in dimethylsulfoxide (12 ml) were addedtriethylamine (1.62 ml) and sulfur trioxide-pyridine complex (1.85 g)under cooling with ice and the mixture was stirred for 1 hour at roomtemperature. The reaction mixture was poured into ice-water and wasextracted with ethyl acetate. The organic layer was washed with 10%aqueous solution of citric acid, water and a saturated aqueous solutionof sodium chloride successively, dried over anhydrous magnesium sulfate,and was concentrated and the residue was dried under reduced pressure togive the title compound (810 mg) having the following physical data.

[0758] TLC: Rf 0.51 (n-hexane:ethyl acetate=3:1);

[0759] NMR (CDCl₃): δ 9.70 (d, J=1.5 Hz, 1H), 5.45-4.98 (br, 1H),4.07-3.86 (m, 1H), 2.82-2.58 (m, 1H), 2.06-1.85 (m, 1H), 1.82-1.19 (m,7H), 1.43 (s, 9H).

REFERENCE EXAMPLE 4

[0760] (1R,2S)-2-(t-butoxycarbonylamino)cyclohexanecarboxylic acid

[0761] To a solution of the compound prepared in reference example 3(810 mg) in t-butanol (6.2 ml)-water (6.2 ml) were added2-methyl-2-butene (1.85 ml), sodium dihydrogenphosphate dihydrate (723mg) and sodium chlorite (80%, 1.53 g) under cooling with ice and themixture was stirred for 2 hours at room temperature. To the reactionmixture was added 10% aqueous solution of citric acid and was extractedwith ethyl acetate. The organic layer was washed with 10% aqueoussolution of citric acid, water and a saturated aqueous solution ofsodium chloride successively, dried over anhydrous magnesium sulfate andwas concentrated. The residue was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=3:1) to give the title compound (734mg) having the following physical data.

[0762] TLC: Rf 0.21 (n-hexane:ethyl acetate=3:1);

[0763] NMR (CD₃OD): δ 3.96-3.78 (m, 1H), 2.77-2.59 (m, 1H), 2.05-1.17(m, 8H), 1.43 (s, 9H)

EXAMPLE 4

[0764]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(t-butoxycarbonylamino)cyclohexyl]carboxamide

[0765] To a solution of the compound prepared in reference example 4(374 mg) in dimethylformamide (5 ml) was added the compound prepared inexample 2 (243 mg) and 1-hydroxybenzotriazole (199 mg) and1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (211 mg)and triethylamine (0.28 ml) and the mixture was stirred for 4 hours atroom temperature. To the reaction mixture was added ethyl acetate andthe mixture was washed with a saturated aqueous solution of sodiumbicarbonate, water and a saturated aqueous solution of sodium chloridesuccessively, dried over anhydrous magnesium sulfate and wasconcentrated. The residue was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=2:1) to give the compound of thepresent invention (352 mg) having the following physical data.

[0766] TLC: Rf 0.24 (hexane:ethyl acetate=1:1);

[0767] NMR (CDCl₃): δ 7.25-6.97 (m, 4H), 6.22 and 6.07 (each d, J=8.1Hz, totally 1H), 5.49 and 5.23 (each d, J=7.8 Hz, totally 1H), 4.75-4.60(m, 1H), 3.98 (s, 2H), 3.87-3.66 (m, 1H), 3.45-3.34 (m, 2H), 3.32-3.08(m, 2H), 3.00-2.80 (m, 2H), 2.67-2.53 (m, 1H), 2.08-1.15 (m, 13H),1.43and 1.41 (each s, totally 9H), 0.99-0.78 (m, 6H)

EXAMPLE 5

[0768]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-aminocyclohexyl]carboxamide dihydrochloride

[0769] By the same procedure as described in example 2 using thecompound prepared in example 4 in place of the compound prepared inexample 1, the compound of the present invention having the followingphysical data was obtained.

[0770] TLC: Rf 0.83 (chloroform:methanol:28% ammonia water=8:2:0.4);

[0771] NMR (CD₃OD): δ 7.46-7.09 (m, 4H), 4.62-4.15 (m, 5H), 3.75-3.54(m, 2H), 3.54-3.42 (m, 1H), 3.20-2.95 (m, 2H), 2.95-2.79 (m, 1H),2.19-1.38 (m, 13H), 0.98 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H).

EXAMPLE 6

[0772]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-chlorophenylcarbonylamino)cyclohexyl]carboxamide

[0773] To a suspension of the compound prepared in example 5 indichloroethane (4 ml) was added triethylamine (0.33 ml) and the mixturewas stirred for 15 minutes at room temperature. Thereto was added4-chlorobenzoyl chloride (148 mg) and the mixture was stirred foranother 4 hours. To the reaction mixture was added ethyl acetate and waswashed with a saturated aqueous solution of sodium bicarbonate, waterand a saturated aqueous solution of sodium chloride successively. Theorganic layer was dried over anhydrous magnesium sulfate and wasconcentrated. The residue was purified by column chromatography onsilica gel (ethyl acetate:n-hexane=2:1) to give the compound of thepresent invention (284 mg) having the following physical data.

[0774] TLC: Rf 0.51 (ethyl acetate);

[0775] NMR (CDCl₃): δ 7.79 and 7.71 (each d, J=9.0 Hz, totally 2H), 7.61(d, J=9.0 Hz, 0.3H), 7.44-7.33 (m, 2.7H), 7.21-6.97 (m, 4H), 6.14 and6.07 (each d, J=8.4 Hz, totally 1H), 4.78-4.62 (m, 1H), 4.34-4.16 (m,1H), 4.04-3.86 (m, 2H), 3.38-3.20 (m, 2H), 3.20-3.07 (m, 2H), 3.02-2.83(m, 2H), 2.79-2.68 (m, 1H), 2.19-1.15 (m, 13H), 0.88, 0.87, 0.77 and0.75 (each d, J=6.6 Hz, totally 6H).

EXAMPLE 6(1)-EXAMPLE 6(27)

[0776] By the same procedure as described in example 6 using ahalogenated compound corresponding to 4-chlorobenzoylchloride, thecompound of the present invention having the following physical data wasobtained.

EXAMPLE 6(1)

[0777]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-phenylacetylaminocyclohexyl]carboxamide

[0778] TLC: Rf 0.66 (chloroform:methanol=9:1);

[0779] NMR (CDCl₃): δ 7.35-7.00 (m, 9H), δ 63 and 6.44 (each d, J=8.4and 8.1 Hz, totally 1H), 6.08 (d, J=8.4 Hz, 1H), 4.70-4.50 (m, 1H),4.20-4.00 (m, 1H), 3.99 and 3.98 (each s, totally 2H), 3.65-3.45 (m,2H), 3.35-3.20 (m, 2H), 3.20-3.10 (m, 2H), 2.95-2.85 (m, 2H), 2.56 (q,J=5.2 Hz, 1H), 1.90-1.15 (m, 13H), 0.90-0.75 (m, 6H).

EXAMPLE 6(2)

[0780]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-hydrocinnamoylaminocyclohexyl]carboxamide

[0781] TLC: Rf 0.68 (chloroform:methanol=9:1);

[0782] NMR (CDCl₃): δ 7.35-6.95 (m, 9H), 6.61 and 6.39 (each d, J=8.8and 8.0 Hz, totally 1H), 6.07 and 5.92 (each d, J=8.6 and 7.6 Hz,totally 1H), 4.75-4.55 (m, 1H), 4.20-3.90 (m, 1H), 3.98 (s, 2H), 3.32(s, 2H), 3.25-3.10 (m, 2H), 3.05-2.75 (m, 4H), 2.60-2.35 (m, 3H),2.00-1.10 (m, 13H), 1.00-0.70 (m, 6H).

EXAMPLE 6(3)

[0783]N-[5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-acetylaminocyclohexyl]carboxamide

[0784] TLC: Rf 0.62 (chloroform:methanol=9:1);

[0785] NMR (CDCl₃): δ 7.40-7.00 (m, 4H), 6.65 and 6.43 (each d, J=8.8and 8.2 Hz, totally 1H), 6.15 (d, J=7.8 Hz, 1H), 4.75-4.55 (m, 1H),4.20-3.95 (m, 1H), 3.99 (s, 2H), 3.34 and 3.32 (each s, totally 2H),3.25-3.10 (m, 2H), 3.00-2.80 (m, 2H), 2.75-2.55 (m, 1H), 2.25-1.20 (m,13H), 2.01 and 1.93 (each s, totally 3H), 1.05-0.75 (m, 6H).

EXAMPLE 6(4)

[0786]N-[5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(6-aminonicotinoyl)aminocyclohexyl]carboxamide

[0787] TLC: Rf 0.40 (chloroform:methanol=9:1);

[0788] NMR (CDCl₃): δ 8.57 and 8.49 (each d, J=2.0 Hz, totally 1H), 7.92and 7.83 (each dd, J=8.8 and 2.0 Hz, totally 1H), 7.60-7.30 (m, 1H),7.25-6.95 (m, 4H), 6.47 and 6.44 (each d, J=8.8 Hz, totally 1H),6.24-6.00 (m, 1H), 4.89 (brs, 2H), 4.85-4.54 (m, 1H), 4.40-4.13 (m, 1H),3.98 and 3.95 (each s, totally 2H), 3.32 (s, 2H), 3.25-3.04 (m, 2H),3.00-2.83 (m, 2H), 2.83-2.62 (m, 1H), 2.19-1.08 (m, 13H), 0.87, 0.86,0.78, and 0.76 (each d, J=6.4 Hz, totally 6H)

EXAMPLE 6(5)

[0789]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-(t-butoxycarbonyl)piperazin-1-ylcarbonylamino)cyclohexyl]carboxamide

[0790] TLC: Rf 0.38 (ethyl acetate);

[0791] NMR (CDCl₃): δ 7.23-6.98 (m, 4H), 6.16 (d, J=8.7 Hz, 1H), 5.76(d, J=7.7 Hz, 1H), 4.75-4.63 (m, 1H), 4.02-3.86 (m, 1H), 3.97 (brs, 2H),3.48-3.36 (m, 4H), 3.36-3.25 (m, 4H), 3.32 (s, 2H), 3.22-3.12 (m, 2H),2.96-2.86 (m, 2H), 2.70-2.57 (m, 1H), 2.03-1.24 (m, 13H), 1.46 (s, 9H),0.87 (d, J=6.6 Hz, 3H), 0.85 (d, J=6.6 Hz, 3H).

EXAMPLE 6(6)

[0792]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(quinoxalin-2-ylcarbonylamino)cyclohexyl]carboxamide

[0793] TLC: Rf 0.44 (ethyl acetate);

[0794] NMR (CDCl₃): δ 9.65 and 9.64 (each s, totally 1H), 8.77 and 8.63(each d, J=8.4 Hz, totally 1H), 8.24-8.10 (m, 2H), 7.94-7.76 (m, 2H),7.25-6.87 (m, 4H), 6.25 and 6.12 (each d, J=8.4 Hz, totally 1H),4.78-4.63 (m, 1H), 4.51-4.32 (m, 1H), 3.96 and 3.83 (each s, totally2H), 3.34-3.18 (m, 2H), 3.18-3.10 and 3.04-2.85 (each m, totally 4H),2.85-2.73 (m, 1H), 2.34-1.10 (m, 13H), 0.86, 0.85, 0.62 and 0.58 (eachd, J=6.3 Hz, totally 6H).

EXAMPLE 6(7)

[0795]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-naphthoylaminocyclohexyl]carboxamide

[0796] TLC: Rf 0.47 (ethyl acetate);

[0797] NMR (CDCl₃): δ 8.39 and 8.29 (each s, totally 1H), 7.99-7.79 (m,4H), 7.70 and 7.43 (each d, J=7.5 Hz, totally 1H), 7.61-7.48 (m, 2H),7.22-6.89 (m, 4H), 6.17 and 6.11 (each d, J=8.4 Hz, totally 1H),4.79-4.61 (m, 1H), 4.44-4.26 (m, 1H), 4.03-3.88 (m, 2H), 3.37-3.22 (m,2H), 3.21-3.05 (m, 2H), 3.01-2.87 (m, 2H), 2.87-2.76 (m, 1H), 2.20-1.10(m, 13H), 0.86, 0.85, 0.72 and 0.71 (each d, J=6.6 Hz, totally 6H).

EXAMPLE 6(8)

[0798]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(1-benzothiophen-2-ylcarbonylamino)cyclohexyl]carboxamide

[0799] TLC: Rf 0.56 (ethyl acetate);

[0800] NMR (CDCl₃): δ 7.90-7.75 (m, 2H), 7.72 (s, 1H), 7.45-7.31 (m,3H), 7.23-6.94 (m, 4H), 6.14 and 6.08 (each d, J=8.1 Hz, totally 1H),4.79-4.62 (m, 1H), 4.36-4.16 (m, 1H), 4.02-3.88 (m, 2H), 3.33 (s, 2H),3.22-3.06 (m, 2H), 3.02-2.81 (m, 2H), 2.81-2.72 (m, 1H), 2.20-1.12 (m,13H), 0.87, 0.86, 0.76 and 0.75 (each d, J=6.3 Hz, totally 6H)

EXAMPLE 6(9)

[0801]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-methoxybenzoylamino)cyclohexyl]carboxamide

[0802] TLC: Rf 0.43 (ethyl acetate);

[0803] NMR (CDCl₃): δ 7.81 and 7.73 (each d, J=9.0 Hz, totally 2H), 7.44(d, J=8.4 Hz, 0.3H), 7.23-6.95 (m, 4.7H), 6.90 (d, J=9.0 Hz, 2H), 6.14and 6.10 (each d, J=8.4 Hz, totally 1H), 4.76-4.60 (m, 1H), 4.34-4.18(m, 1H), 3.97 and 3.93 (each brs, totally 2H), 3.84 and 3.83 (each s,totally 3H), 3.37-3.21 (m, 2H), 3.21-3.06 (m, 2H), 3.01-2.82 (m, 2H),2.80-2.69 (m, 1H), 2.18-1.12 (m, 13H), 0.87, 0.75 and 0.74 (each d,J=6.3 Hz, totally 6H).

EXAMPLE 6(10)

[0804]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-nitrobenzoylamino)cyclohexyl]carboxamide

[0805] TLC: Rf 0.51 (ethyl acetate);

[0806] NMR (CDCl₃): δ 8.31-8.21 (m, 2H), 8.01 and 7.94 (each d, J=9.0Hz, totally 2H), 7.85 and 7.76 (each d, J=7.5 Hz, totally 1H), 7.23-6.96(m, 4H), 6.17 and 6.08 (each d, J=8.4 Hz, totally 1H), 4.80-4.66 (m,1H), 4.36-4.18 (m, 1H), 4.06-3.88 (m, 2H), 3.40-3.24 (m, 2H), 3.24-3.07(m, 2H), 3.02-2.84 (m, 2H), 2.80-2.70 (m, 1H), 2.20-1.20 (m, 13H), 0.89,0.88, 0.80 and 0.78 (each d, J=6.6 Hz, totally 6H).

EXAMPLE 6(11)

[0807]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-phenylbenzoylamino)cyclohexyl]carboxamide

[0808] TLC: Rf 0.33 (ethyl acetate);

[0809] NMR (CDCl₃): δ 7.92 and 7.84 (each d, J=9.0 Hz, totally 2H),7.70-7.55 (m, 4H), 7.51-7.30 (m, 4H), 7.23-6.97 (m, 4H), 6.20-6.09 (m,1H), 4.79-4.63 (m, 1H), 4.42-4.20 (m, 1H), 3.98 and 3.95 (each s,totally 2H), 3.40-3.21 (m, 2H), 3.21-3.03 (m, 2H), 3.03-2.81 (m, 2H),2.81-2.69 (m, 1H), 2.20-1.12 (m, 13H), 0.87 and 0.76 (each d, J=6.6 Hz,totally 6H).

EXAMPLE 6(12)

[0810]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-fluorobenzoylamino)cyclohexyl]carboxamide

[0811] TLC: Rf 0.36 (ethyl acetate);

[0812] NMR (CDCl₃): δ 7.89-7.73 (m, 2H), 7.57 and 7.33 (each d, J=8.1Hz, totally 1H), 7.22-6.97 (m, 6H), 6.13 and 6.08 (each d, J=8.1 Hz,totally 1H), 4.77-4.62 (m, 1H), 4.34-4.16 (m, 1H), 3.98 and 3.95 (eachs, totally 2H), 3.32 (s, 2H), 3.23-3.08 (m, 2H), 3.03-2.84 (m, 2H),2.79-2.67 (m, 1H), 2.15-1.16 (m, 13H), 0.88, 0.87, 0.77 and 0.75 (eachd, J=6.6 Hz, totally 6H).

EXAMPLE 6(13)

[0813]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(2-pyridylcarbonylamino)cyclohexyl]carboxamide

[0814] TLC: Rf 0.28 (ethyl acetate);

[0815] NMR (CDCl₃): δ 8.60 (d. J=8.4 Hz, 1H), 8.55 (ddd, J=5.0, 2.0 and1.2 Hz, 1H), 8.14 (dt, J=7.8 and 1.2 Hz, 1H), 7.82 (dt, J=2.0 and 7.8Hz, 1H), 7.40 (ddd, J=7.8, 5.0 and 1.2 Hz, 1H), 7.23-6.96 (m, 4H), 6.17(d, J=8.4 Hz, 1H), 4.72-4.59 (m, 1H), 4.44-4.30 (m, 1H), 3.96 (s, 2H),3.34 (d, J=18.3 Hz, 1H), 3.27 (d, J=18.3 Hz, 1H), 3.20-3.08 (m, 2H),2.96-2.83 (m, 2H), 2.79-2.68 (m, 1H), 2.20-1.10 (m, 13H), 0.65 and 0.63(each d, J=6.0 Hz, totally 6H)

EXAMPLE 6(14)

[0816]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-t-butylbenzoylamino)cyclohexyl]carboxamide

[0817] TLC: Rf 0.39 (ethyl acetate);

[0818] NMR (CDCl₃): δ 7.77 and 7.70 (each d, J=9.0 Hz, totally 2H), 7.49(d, J=8.0 Hz, 0.3H), 7.42 (d, J=9.0 Hz, 2H), 7.25-6.94 (m, 4.7H), 6.14(d, J=8.4 Hz, 1H), 4.74-4.60 (m, 1H), 4.36-4.20 (m, 1H), 3.98 and 3.95(each s, totally 2H), 3.33 and 3.30 (each s, totally 2H), 3.22-3.07 (m,2H), 3.00-2.84 (m, 2H), 2.79-2.69 (m, 1H), 2.15-1.18 (m, 13H), 1.32 and1.31 (each s, totally 9H), 0.86 and 0.74 (each d, J=6.3 Hz, totally 6H).

EXAMPLE 6(15)

[0819]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(2-methylthionicotinoylamino)cyclohexyl]carboxamide

[0820] TLC: Rf 0.32 (ethyl acetate);

[0821] NMR (CDCl₃): δ 8.53-8.44 (m, 1H), 7.78 and 7.73 (each dd, J=7.7and 1.7 Hz, totally 1H), 7.45 (d, J=9.6 Hz, 0.3H), 7.25-6.92 (m, 5.7H),6.19 and 6.12 (each d, J=8.4 Hz, totally 1H), 4.74-4.58 (m, 1H),4.40-4.24 (m, 1H), 4.01-3.82 (m, 2H), 3.31 and 3.27 (each s, totally2H), 3.21-3.06 (m, 2H), 3.01-2.84 (m, 2H), 2.81-2.70 (m, 1H), 2.54 (s,3H), 2.20-1.20 (m, 13H), 0.88, 0.85, 0.80 and 0.77 (each d, J=6.6 Hz,totally 6H).

EXAMPLE 6(16)

[0822]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(1-naphthylacetylamino)cyclohexyl]carboxamide

[0823] TLC: Rf 0.29 (ethyl acetate);

[0824] NMR (CDCl₃): δ 8.07-7.92 (m, 1H), 7.89-7.74 (m, 2H), 7.55-7.30(m, 4H), 7.22-6.97 (m, 4H), 6.58 and 6.41 (each d, J=8.7 Hz, totally1H), 6.05 (br, 0.3H), 6.00 (d, J=7.8 Hz, 0.7H), 4.60-4.45 (m, 1H),4.21-3.76 (m, 5H), 3.27 (s, 2H), 3.20-3.08 (m, 2H), 3.01-2.85 (m, 2H),2.54-2.39 (m, 1H), 1.90-1.05 (m, 13H), 0.89, 0.86, 0.85 and 0.81 (eachd, J=6.3 Hz, totally 6H).

EXAMPLE 6(17)

[0825]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(2-fluorobenzoylamino)cyclohexyl]carboxamide

[0826] TLC: Rf 0.42 (ethyl acetate);

[0827] NMR (CDCl₃): δ 8.07-7.98 (m, 1H), 7.83-7.65 and 7.65-7.34 (eachm, totally 2H), 7.30-6.94 (m, 6H), 6.21 and 6.11 (each d, J=8.4 Hz,totally 1H), 4.77-4.63 (m, 1H), 4.46-4.28 (m, 1H), 3.96 and 3.91 (eachs, totally 2H), 3.40-3.21 (m, 2H), 3.21-3.04 (m, 2H), 2.96-2.82 (m, 2H),2.80-2.68 (m, 1H), 2.20-1.16 (m, 13H), 0.88, 0.87 and 0.72 (each d,J=6.3 Hz, totally 6H).

EXAMPLE 6(18)

[0828]N-[(3S)-1-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)-5-methyl-2-oxo-6-hexyl]-1-[(1R,2S)-2-(6-chloronicotinoylamino)cyclohexyl]carboxamide

[0829] TLC: Rf 0.32 (ethyl acetate);

[0830] NMR (CDCl₃): δ 8.85 and 8.77 (each d, J=2.7 Hz, totally 1H), 8.12and 8.04 (each dd, J=8.4 and 2.7 Hz, totally 1H), 7.80 and 7.71 (each d,J=7.5 Hz, totally 1H), 7.38 and 7.37 (each d, J=8.4 Hz, totally 1H),7.23-6.95 (m, 4H), 6.14 and 6.03 (each d, J=8.4 Hz, totally 1H),4.81-4.64 (m, 1H), 4.34-4.15 (m, 1H), 4.06-3.85 (m, 2H), 3.32 and 3.31(each s, totally 2H), 3.24-3.07 (m, 2H), 3.02-2.84 (m, 2H), 2.79-2.66(m, 1H), 2.15-1.17 (m, 13H), 0.89, 0.87, 0.81 and 0.79 (each d, J=6.3Hz, totally 6H).

EXAMPLE 6(19)

[0831]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-trifluoromethylbenzoylamino)cyclohexyl]carboxamide

[0832] TLC: Rf 0.41 (ethyl acetate);

[0833] NMR (CDCl₃): δ 7.96 and 7.88 (each d, J=8.1 Hz, totally 2H), 7.68(d, J=8.1 Hz, 2H), 7.57 (d, J=7.5 Hz, 1H), 7.24-6.96 (m, 4H), 6.15 (d,J=7.8 Hz, 1H), 4.78-4.65 (m, 1H), 4.35-4.18 (m, 1H), 4.06-3.90 (m, 2H),3.33 (s, 2H), 3.25-3.04 (m, 2H), 3.04-2.84 (m, 2H), 2.80-2.67 (m, 1H),2.18-1.20 (m, 13H), 0.88, 0.87, 0.78 and 0.76 (each d, J=6.6 Hz, totally6H).

EXAMPLE 6(20)

[0834]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-cyanobenzoylamino)cyclohexyl]carboxamide

[0835] TLC: Rf 0.36 (ethyl acetate);

[0836] NMR (CDCl₃): δ 7.95 and 7.88 (each d, J=9.0 Hz, totally 2H),7.77-7.64 (m, 3H), 7.24-6.96 (m, 4H), 6.16 and 6.09 (each d, J=8.4 Hz,totally 1H), 4.79-4.65 (m, 1H), 4.32-4.17 (m, 1H), 4.05-3.90 (m, 2H),3.32 and 3.31 (each s, totally 2H), 3.25-3.04 (m, 2H), 3.04-2.82 (m,2H), 2.77-2.65 (m, 1H), 2.18-1.18 (m, 13H), 0.89, 0.88, 0.79 and 0.77(each d, J=6.3 Hz, totally 6H).

EXAMPLE 6(21)

[0837]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-methylbenzoylamino)cyclohexyl]carboxamide

[0838] TLC: Rf 0.32 (ethyl acetate);

[0839] NMR (CDCl₃): δ 7.73 and 7.65 (each d, J=8.1 Hz, totally 2H), 7.49(d, J=7.8 Hz, 0.2H), 7.24-6.96 (m, 6.8H), 6.15 (d, J=8.4 Hz, 1H),4.76-4.61 (m, 1H), 4.34-4.19 (m, 1H), 3.98 and 3.94 (each s, totally2H), 3.43-3.21 (m, 2H), 3.21-3.05 (m, 2H), 3.03-2.81 (m, 2H), 2.81-2.67(m, 1H), 2.38 (s, 3H), 2.22-1.15 (m, 13H), 0.86, 0.75 and 0.74 (each d,J=6.6 Hz, totally 6H)

EXAMPLE 6(22)

[0840]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-trifluoromethyloxybenzoylamino)cyclohexyl]carboxamide

[0841] TLC: Rf 0.41 (ethyl acetate);

[0842] NMR (CDCl₃): δ 7.90 and 7.82 (each d, J=8.7 Hz, total 2H), 7.65and 7.44 (each d, J=7.8 Hz, total 1H), 7.34-6.93 (m, 6H), 6.15 (d, J=8.1Hz, 1H), 4.78-4.62 (m, 1H), 4.34-4.17 (m, 1H), 4.06-3.90 (m, 2H), 3.33(s, 2H), 3.25-3.06 (m, 2H), 3.03-2.82 (m, 2H), 2.82-2.65 (m, 1H),2.20-1.15 (m, 13H), 0.87, 0.77 and 0.75 (each d, J=6.3 Hz, total 6H).

EXAMPLE 6(23)

[0843]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(3-t-butyl-1-methylpyrazol-5-ylcarbonylamino)cyclohexyl]carboxamide

[0844] TLC: Rf 0.42 (ethyl acetate);

[0845] NMR (CDCl₃): δ 7.37 (d, J=9.0 Hz, 0.2H), 7.22-6.98 (m, 4.8H),6.49 and 6.31 (each s, total 1H), 6.12 and 6.05 (each d, J=8.1 Hz, total1H), 4.80-4.64 (m, 1H), 4.28-4.05 (m, 1H), 4.12 and 4.09 (each s, total3H), 4.05-3.90 (m, 2H), 3.33 (s, 2H), 3.24-3.08 (m, 2H), 3.03-2.84 (m,2H), 2.80-2.65 (m, 1H), 2.15-1.13 (m, 13H), 1.29 and 1.28 (each s, total9H), 0.88, 0.87, 0.80 and 0.79 (each d, J=6.3 Hz, total 6H).

EXAMPLE 6(24)

[0846]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(N,N-di-n-propyl-4-sulfamoyl)benzoylamino)cyclohexyl]carboxamide

[0847] TLC: Rf 0.42 (ethyl acetate);

[0848] NMR (CDCl₃): δ 7.89 (d, J=8.7 Hz, 2H), 7.84 (d, J=8.7 Hz, 2H),7.60 (d, J=7.8 Hz, 1H), 7.25-6.96 (m, 4H), 6.19 (d, J=8.4 Hz, 1H),4.80-4.66 (m, 1H), 4.36-4.18 (m, 1H), 3.99 (s, 2H), 3.34 (s, 2H),3.25-3.13 (m, 2H), 3.13-3.00 (m, 4H), 2.97-2.84 (m, 2H), 2.80-2.68 (m,1H), 2.13-1.20 (m, 17H), 0.87 (t, J=7.5 Hz, 6H), 0.79 and 0.76 (each d,J=6.3 Hz, total 6H).

EXAMPLE 6(25)

[0849]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-mesylaminocyclohexyl]carboxamide

[0850] TLC: Rf 0.39 (ethyl acetate);

[0851] NMR (CDCl₃): δ 7.24-6.99 (m, 4H), 6.30 and 5.64 (each d, J=7.5Hz, total 1H), 6.08 (d, J=8.1 Hz, 1H), 4.77-4.62 (m, 1H), 3.97 (s, 2H),3.74-3.56 (m, 1H), 3.34 and 3.32 (each s, total 2H), 3.22-3.12 (m, 2H),3.00-2.85 (m, 2H), 2.98and 2.92 (each s, total 3H), 2.76-2.59 (m, 1H),2.17-1.20 (m, 13H), 0.96-0.80 (m, 6H).

EXAMPLE 6(26)

[0852]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-phenylsulfonylaminocyclohexyl]carboxamide

[0853] TLC: Rf 0.58 (ethyl acetate);

[0854] NMR (CDCl₃): δ 7.92-7.82 (m, 2H), 7.60-7.40 (m, 3H), 7.23-6.98(m, 4H), 6.14 (d, J=6.6 Hz, 1H), 6.11-5.96 (br, 1H), 4.71-4.56 (m, 1H),4.00 (s, 2H), 3.52-3.24 (brs, 3H), 3.24-3.11 (m, 2H), 3.02-2.83 (m, 2H),2.52-2.40 (m, 1H), 2.02-1.17 (m, 13H), 0.88 and 0.86 (each d, J=6.3 Hz,total 6H).

EXAMPLE 6(27)

[0855]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-dimethylaminobenzoylamino)cyclohexyl]carboxamide

[0856] TLC: Rf 0.19 (ethyl acetate);

[0857] NMR (CDCl₃): δ 7.75 and 7.66 (each d, J=9.2 Hz, total 2H),7.32-7.24 and 7.22-6.87 (each m, total 5H), 6.65 (d, J=9.2 Hz, 2H),6.23-6.04 (m, 1H), 4.77-4.54 (m, 1H), 4.40-4.16 (m, 1H), 3.97 and 3.93(each brs, total 2H), 3.39-3.22 (m, 2H), 3.22-3.04 (m, 2H), 3.00 and2.99 (each s, total 6H), 2.97-2.81 (m, 2H), 2.81-2.65 (m, 1H), 2.17-1.14(m, 13H), 0.86 and 0.73 (each d, J=6.0 Hz, total 6H).

EXAMPLE 7

[0858]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(piperazin-1-ylcarbonylamino)cyclohexyl]carboxamide dihydrochloride

[0859] By the same procedure as described in example 2 using thecompound prepared in example 6 (5) in place of the compound prepared inexample 1, the compound of the present invention having the followingphysical data was obtained.

[0860] TLC: Rf 0.22 (chloroform:methanol:acetic acid=10:2:1);

[0861] NMR (CD₃OD): δ 7.48-7.20 (m, 4H), 4.47 (brs, 2H), 4.34 (dd,J=10.2 and 4.8 Hz, 1H), 4.31-4.01 (m, 3H), 3.71-3.47 (m, 6H), 3.19 (t,J=5.4 Hz, 4H), 3.12-3.01 (m, 2H), 2.75-2.56 (m, 1H), 2.18-1.16 (m, 13H),0.96 (d, J=6.3 Hz, 3H), 0.88 (d, J=6.3 Hz, 3H).

EXAMPLE 8

[0862](3S)-3-(t-butoxycarbonylamino)-5-methyl-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)hexan-2-one

[0863] To a solution of the compound prepared in Reference Example 1(3.08 g) and 2,3,4,5-tetrahydro-1H-1-benzazepine (2.21 g) inacetonitrile (28 ml) was added diisopropylethylamine (2.61 ml) at 0° C.and the mixture was stirred at room temperature for 62 hours. To thereaction mixture was added water and was extracted with ethyl acetate.The organic layer was washed with a saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate and was concentrated. Theresidue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=10:1) to give the compound of the presentinvention (3.16 g) having the following physical data.

[0864] TLC: Rf 0.50 (n-hexane:ethyl acetate 7:3);

[0865] NMR (CDCl₃): δ 7.11 (d, J=7.2 Hz, 1H), 7.10 (t, J=7.2 Hz, 1H),6.88 (t, J=7.2 Hz, 1H), 6.75 (d, J=7.2 Hz, 1H), 5.00 (d, J=8.4 Hz, 1H),4.59 (m, 1H), 4.15 (d, J=15.3 Hz, 1H), 4.10 (d, J=15.3 Hz, 1H),3.00-2.80 (m, 4H), 1.89-1.30 (m, 4H), 1.43 (s, 9H), 0.96 (d, J=6.3 Hz,3H), 0.90 (d, J=6.3 Hz, 3H)

EXAMPLE 9

[0866](3S)-3-amino-5-methyl-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)hexan-2-onedihydrochloride

[0867] By the same procedure as described in example 2 using thecompound prepared in example 8 in place of the compound prepared inexample 1, the compound of the present invention having the followingphysical data was obtained as a crude product. The crude product wasused in the next reaction without further purification.

[0868] TLC: Rf 0.35 (chloroform:methanol:water=10:1:0.1).

EXAMPLE 10-EXAMPLE 10 (9)

[0869] By the same procedure as described in example 3 using thecompound prepared in example 9 in place of the compound prepared inexample 2 and (−)-2-benzamidocyclohexanecarboxylic acid or acorresponding carboxylic acid thereto, the compound of the presentinvention having the following physical data was obtained.

EXAMPLE 10

[0870]N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

[0871] TLC: Rf 0.35 (n-hexane:ethyl acetate=3:1);

[0872] NMR (CDCl₃): δ 7.78 (dd, J=7.6, 1.8 Hz, 1H), 7.50-7.36 (m, 3H),7.24 (d, J=9.6 Hz, 1H), 7.14-7.06 (m, 2H), 6.89 (dt, J=1.8, 7.6 Hz, 1H),6.75 (d, J=7.6 Hz, 1H), 6.13 (d, J=8.4 Hz, 1H), 4.96 (dt, J=3.4, 8.4 Hz,1H), 4.29 (m, 1H), 4.16 (d, J=17.2 Hz, 1H), 4.08 (d, J=17.2 Hz, 1H),3.00-2.68 (m, 4H), 2.20-2.00 (m, 1H), 2.00-1.10 (m, 15H), 0.82 (d, J=6.0Hz, 3H), 0.76 (d, J=6.0 Hz, 3H).

EXAMPLE 10(1)

[0873](2S)-N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

[0874] TLC: Rf 0.50 (chloroform:ethyl acetate=9:1);

[0875] NMR (CDCl₃): δ 7.34 (m, 5H), 7.10 (m, 2H), 6.89 (dt, J=0.9, 7.5Hz, 1H), 6.74 (d, J=7.5 Hz, 1H), 6.38 (brd, J=8.4 Hz, 1H), 5.10 (m, 3H),4.96 (ddd, J=9.9, 8.4, 3.9 Hz, 1H), 4.20-4.00 (m, 3H), 3.02-2.78 (m,2H), 1.92-1.60 (m, 10H), 1.00-0.85 (m, 12H).

EXAMPLE 10(2)

[0876]N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-1-cyclohexylcarboxamide

[0877] TLC: Rf 0.70 (n-hexane:ethyl acetate=7:3);

[0878] NMR (CDCl₃): δ 7.11 (d, J=7.2 Hz, 1H), 7.10 (dt, J=1.8, 7.2 Hz,1H), 6.89 (dt, J=1.8, 7.2 Hz, 1H), 6.75 (d, J=7.2 Hz, 1H), 5.87 (d,J=8.4 Hz, 1H), 4.97 (ddd, J=10.2, 8.4, 3.9 Hz, 1H), 4.14 (d, J=17.4 Hz,1H), 4.06 (d, J=17.4 Hz, 1H), 3.05-2.77 (m, 4H), 2.09 (tt, J=11.4, 3.3Hz, 1H), 1.90-1.20 (m, 17H), 0.95 (d, J=6.3 Hz, 3H) and 0.90 (d, J=6.3Hz, 3H).

EXAMPLE 10(3)

[0879]N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-4-benzyloxybenzamide

[0880] TLC: Rf 0.60 (n-hexane:ethyl acetate=7:3);

[0881] NMR (CDCl₃): δ 7.73 (d, J=8.7 Hz, 2H), 7.48-7.32 (m, 5H),7.14-7.08 (m, 2H), 6.99 (d, J=8.7 Hz, 2H), 6.89 (dt, J=1.8, 7.6 Hz, 1H),6.78 (d, J=7.6 Hz, 1H), 6.54 (d, J=8.7 Hz, 1H), 5.20 (m, 1H), 5.11 (s,2H), 4.22 (d, J=17.1 Hz, 1H), 4.18 (d, J=17.1 Hz, 1H), 3.18-2.78 (m,4H), 1.99-1.43 (m, 7H), 1.00 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H).

EXAMPLE 10(4)

[0882]N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-3-benzyloxybenzamide

[0883] TLC: Rf 0.65 (n-hexane:ethyl acetate=7:3);

[0884] NMR (CDCl₃): δ 7.50-7.20 and 7.20-7.05 (each m, totally 11H),6.90 (dt, J=1.8, 7.6 Hz, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.62 (d, J=8.0 Hz,1H), 5.30-5.18 (m, 1H), 5.11 (s, 2H), 4.20 (d, J=17.2 Hz, 1H), 4.13 (d,J=17.2 Hz, 1H), 3.10-2.80 (m, 4H), 1.95-1.40 (m, 7H), 1.02 (d, J=6.2 Hz,3H), 0.93 (d, J=6.2 Hz, 3H).

EXAMPLE 10(5)

[0885]N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-2-benzyloxybenzamide

[0886] TLC: Rf 0.55 (n-hexane:ethyl acetate=7:3);

[0887] NMR (CDCl₃): δ 8.26 (d, J=7.2 Hz, 1H), 8.21 (dd, J=7.8, 1.8 Hz,1H), 7.52-7.38 (m, 6H), 7.13-7.05 (m, 4H), 6.85 (t, J=7.2 Hz, 1H), 6.73(d, J=7.2 Hz, 1H), 5.19 (d, J=10.5 Hz, 1H), 5.16 (d, J=10.5 Hz, 1H),4.96-4.89 (m, 1H), 4.19 (d, J=17.7 Hz, 1H), 4.12 (d, J=17.7 Hz, 1H),3.09-2.72 (m, 4H), 1.90-1.05 (m, 7H), 0.82 (d, J=6.0 Hz, 3H), 0.67 (d,J=6.0 Hz, 3H)

EXAMPLE 10(6)

[0888]N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-1-[(1S,2R)-2-benzoylaminocyclohexyl]carboxamide

[0889] TLC: Rf 0.25 (n-hexane:ethyl acetate=7:3);

[0890] NMR (CDCl₃): δ 7.80 (dd, J=8.4, 1.8 Hz, 2H), 7.51-7.36 and7.13-7.00 (each m, totally 6H), 6.89 (dt, J=18, 8.0 Hz, 1H), 6.72 (d,J=8.0 Hz, 1H), 6.07 (d, J=8.4 Hz, 1H), 4.91 (ddd, J=10.4, 8.4, 4.4 Hz,1H), 4.29 (m, 1H), 4.11 (d, J=17.2 Hz, 1H), 4.05 (d, J=17.2 Hz, 1H),2.98-2.69 (m, 4H), 2.10-1.25 (m, 16H), 0.94 (d, J=6.2 Hz, 3H), 0.89 (d,J=6.2 Hz, 3H).

EXAMPLE 10(7)

[0891]N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]benzamide

[0892] TLC: Rf 0.60 (n-hexane:ethyl acetate=7:3);

[0893] NMR (CDCl₃): δ 7.78 (dd, J=8.4, 1.8 Hz, 2H), 7.54-7.38 (m, 3H)7.15-7.07 (m, 2H), 6.90 (t, J=7.4 Hz, 1H), 6.79 (d, J=7.4 Hz, 1H), 6.64(d, J=8.0 Hz, 1H), 5.23 (dt, J=4.0, 8.0 Hz, 1H), 4.22 (d, J=16.8 Hz,1H), 4.14 (d, J=16.8 Hz, 1H), 3.10-2.77 (m, 4H), 1.95-1.43 (m, 7H), 1.02(d, J=6.0 Hz, 3H), 0.93 (d, J=6.0 Hz, 3H).

EXAMPLE 10(8)

[0894]N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-3-cyclopentylpropanamide

[0895] TLC: Rf 0.50 (n-hexane:ethyl acetate=7:3);

[0896] NMR (CDCl₃): δ 7.14-7.06 (m, 2H), 6.88 (dt, J=1.8, 8.0 Hz, 1H),6.75 (d, J=8.0 Hz, 1H), 5.95 (d, J=8.0 Hz, 1H), 5.00 (ddd, J=9.8, 8.0,4.0 Hz, 1H), 4.15 (d, J=17.2 Hz, 1H), 4.08 (d, J=17.2 Hz, 1H), 3.08-2.80(m, 4H), 2.20 (dd, J=9.0, 7.6 Hz, 2H), 1.90-1.30 and 1.20-1.00 (each m,totally 18H), 0.95 (d, J=6.4 Hz, 3H), 0.90 (d, J=6.4 Hz, 3H).

EXAMPLE 10(9)

[0897] N-[(3S)-5-methyl-2-oxo-1- (2,3,4,5-tetrahydro-!H-1-benzazepin-1-yl)-3-hexyl]cinnamide

[0898] TLC: Rf 0.60 (n-hexane:ethyl acetate=7:3);

[0899] NMR (CDCl₃): δ 7.62 (d, J=15.6 Hz, 1H), 7.50-7.47 and 7.39-7.34(each m, totally 5H), 7.14-7.09 (m, 2H), 6.88 (dt, J=1.8, 8.1 Hz, 1H),6.79 (d, J=8.1 Hz, 1H), 6.41 (d, J=15.6 Hz, 1H), 6.16 (d, J=8.4 Hz, 1H),5.18 (ddd, J=10.2, 8.4, 4.2 Hz, 1H), 4.15 (d, J=17.1 Hz, 1H), 4.12 (d,J=17.1 Hz, 1H), 3.08-2.78 (m, 4H), 1.98-1.38 (m, 7H), 1.00 (d, J=6.6 Hz,3H), 0.91 (d, J=6.6 Hz, 3H).

EXAMPLE 11

[0900]N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzenesulfonamide

[0901] To a solution of the compound prepared in example 2 (137 mg) indimethylformamide (2 ml) were added benzenesulfonyl chloride (0.07 ml)and triethylamine (0.08 ml) dropwise and the mixture was stirred for 55hours at room temperature. To the reaction mixture was added 10% aqueoussolution of citric acid and was extracted with ethyl acetate. Theorganic layer was washed with a saturated aqueous solution of sodiumbicarbonate, water and a saturated aqueous solution of sodium chloridesuccessively, dried over anhydrous sodium sulfate and was concentrated.The residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=3:1) to give the compound of the presentinvention (10.1 mg) having the following physical data.

[0902] TLC: Rf 0.30 (n-hexane:ethyl acetate=1:1);

[0903] NMR (CDCl₃): δ 7.84 (dd, J=8.7, 1.8 Hz, 2H), 7.60-7.47 (m, 3H),7.20-7.05 (m, 3H), 6.85 (d, J=6.9 Hz, 1H), 5.90-5.30 (br, 1H), 4.08 (dd,J=9.6, 4.2 Hz, 1H), 3.82 (d, J=15.0 Hz, 1H), 3.65 (d, J=15.0 Hz, 1H),3.09 (d, J=18.0 Hz, 1H), 3.05 (d, J=18.0 Hz, 1H), 2.91-2.84 (m, 4H),1.80-1.50 and 1.40-1.20 (each m, totally 5H), 0.84 (d, J=6.6 Hz, 3H),0.75 (d, J=6.6 Hz, 3H).

EXAMPLE 11(1)

[0904]N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]benzenesulfonamide

[0905] By the same procedure as described in example 11 using thecompound prepared in example 9 in place of the compound prepared inexample 2, the compound of the present invention having the followingphysical data was obtained.

[0906] TLC: Rf 0.50 (n-hexane:ethyl acetate=7:3);

[0907] NMR (CDCl₃): δ 7.78 (dd, J=6.9, 1.8 Hz, 2H), 7.56-7.42 (m, 3H)7.10 (dd, J=7.2, 1.8 Hz, 1H), 7.05 (dt, J=1.8, 7.2 Hz, 1H), 6.90 (dt,J=1.8, 7.2 Hz, 1H), 6.57 (d, J=7.2 Hz, 1H), 5.47 (d, J=9.3 Hz, 1H), 4.24(dt, J=3.9, 9.3 Hz, 1H), 3.92 (d, J=17.4 Hz, 1H), 3.81 (d, J=17.4 Hz,1H), 2.85-2.50 (m, 4H), 1.90-1.20 (m, 7H), 0.84 (d, J=6.6 Hz, 6H)

REFERENCE EXAMPLE 5

[0908] 7-hydroxy-1,3,4,5-tetrahydro-2H-2-benzazepin-1-one

[0909] To a solution of 6-hydroxy-1-tetralone (6.5 g) in methanesulfonicacid (140 ml) was added sodium azide (3.4 g) under cooling with ice andthe mixture was stirred for 30 minutes at 0° C. and for 15 hours at roomtemperature. The reaction mixture was poured into ice-water and theretowas added potassium carbonate to alkalify and was extracted withmethylene chloride. The organic layer was washed with water, a saturatedaqueous solution of sodium bicarbonate and a saturated aqueous solutionof sodium chloride successively, dried over anhydrous magnesium sulfateand was concentrated to give the title compound having the followingphysical data as a crude product. The crude product was used in the nextreaction without further purification.

[0910] TLC: Rf 0.39 (chloroform:methanol=9:1).

REFERENCE EXAMPLE 6

[0911] 7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-1-one

[0912] Under atmosphere of argon, to a solution of the compound preparedin reference example 5 (4.79 g) in dimethylformamide (60 ml) were addedpotassium carbonate (11.2 g) and benzyl bromide (3.57 ml) at 0° C. andthe mixture was stirred for 30 minutes at room temperature. To thereaction mixture was added water and was extracted with ethyl acetate.The organic layer was washed with water, a saturated aqueous solution ofsodium bicarbonate and a saturated aqueous solution of sodium chloridesuccessively, and was dried over anhydrous magnesium sulfate and wasconcentrated. The residue was purified by column chromatography onsilica gel (ethyl acetate:n-hexane=3:1) to give the title compound (3.8g) having the following physical data.

[0913] TLC: Rf 0.48 (chloroform:methanol=19:1);

[0914] NMR (CDCl₃): δ 7.67 (d, J=8.4 Hz, 1H), 7.50-7.30 (m, 5H), 6.92(dd, J=8.4, 2.6 Hz 1H), 6.80 (d, J=2.6 Hz, 1H), 6.20 (m, 1H), 5.10 (s,2H), 3.14 (m, 2H), 2.84 (t, J=7.0 Hz, 2H), 2.01 (quintet, J=7.0 Hz, 2H).

REFERENCE EXAMPLE 7

[0915] 7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin hydrochloride

[0916] To a solution of the compound prepared in reference example 6(3.75 g) in tetrahydrofuran (30 ml) was added a suspension of lithiumalminum hydride (1.86 g) in tetrahydrofuran (90 ml) at 0° C. and themixture was stirred for 4 hours at 80° C. To the reaction mixture wasadded ice-water and 15% aqueous solution of sodium hydroxide and themixture was filtered. To the filtrate was added water and was extractedwith methylene chloride. The organic layer was washed with water and asaturated aqueous solution of sodium chloride successively, dried overanhydrous magnesium sulfate to give the title compound having thefollowing physical data as a free compound (3.5 g). A solution thereofin ethyl acetate (20 ml) was added 4N hydrochloric acid-ethyl acetate(20 ml) at 0° C. and the mixture was stirred for 30 minutes at roomtemperature. The reaction mixture was concentrated and the residue waswashed with diethyl ether to give the title compound having thefollowing physical data.

[0917] NMR (DMSO-d₆): δ 8.84 (m, 1H), 7.45-7.24 (m, 6H, O), 6.94 (d,J=2.7 Hz, 1H), 6.84 (dd, J=8.4, 2.7 Hz, 1H), 5.11 (s, 2H), 4.23 (s, 2H),3.30 (m, 2H), 1.82 (m, 2H).

EXAMPLE 12

[0918]1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-(t-butoxycarbonylamino)-5-methyl-2-hexanone

[0919] To a solution of the compound prepared in reference example 7(2.9 g) in a suspension of acetonitrile (30 ml) was addeddiisopropylethylamine (5.22 ml) and the compound prepared in referenceexample 1 (3.1 g) successively and the mixture was stirred for 30minutes at room temperature. To the reaction mixture was added water andwas extracted with ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium bicarbonate and a saturated aqueoussolution of sodium chloride successively, dried over anhydrous magnesiumsulfate and was concentrated. The residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=2:1) to give thecompound of the present invention (4.4 g) having the following physicaldata.

[0920] TLC: Rf 0.31 (hexane:ethyl acetate=3:1);

[0921] NMR (CDCl₃): δ 7.45-7.30 (m, 5H), 6.97 (d, J=8.1 Hz, 1H), 6.80(d, J=2.7 Hz, 1H), 6.60 (dd, J=8.1, 2.7 Hz, 1H), 5.05 (s, 2H), 4.98(brd, J=8.4 Hz, 1H), 4.38 (m, 1H), 3.94 (s, 2H), 3.33 (brs, 2H), 3.16(t, J=5.1 Hz, 2H), 2.85 (t, J=5.4 Hz, 2H), 1.85-1.60 (m, 5H), 1.43 (s,9H), 0.94-0.88 (d, J=6.6 Hz, 6H)

EXAMPLE 13

[0922]3-amino-1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-hexanonedihydrochloride

[0923] By the same procedure as described in example 2 using thecompound prepared in example 12 in place of the compound prepared inexample 1, the compound of the present invention having the followingphysical data was obtained.

[0924] TLC: Rf 0.56 (chloroform:methanol:acetic acid=9:1:1).

EXAMPLE 14

[0925](2S)-N-[(3S)-1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

[0926] To a suspension of the compound prepared in reference example 7(145 mg) in acetonitrile (3 ml) was added diisopropylethylamine (0.19ml) at 0° C. and then was added(2S)-N-[(3S)-1-bromo-5-methyl-2-oxo-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide(250 mg) and the mixture was stirred for 2 hours at room temperature. Tothe reaction mixture was added water and was extracted with ethylacetate. The organic layer was washed with a saturated aqueous solutionof sodium bicarbonate and a saturated aqueous solution of sodiumchloride successively, dried over anhydrous magnesium sulfate and wasconcentrated. The residue was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=7:3) to give the compound of thepresent invention (242 mg) having the following physical data.

[0927] TLC: Rf 0.31 (n-hexane:ethyl acetate=2:1);

[0928] NMR (CDCl₃): δ 7.48-7.23 (m, 10H), 6.94 (m, 1H), 6.79 (d, J=2.7Hz, 1H), 6.68 (dd, J=8.4, 2.7 Hz, 1H), 6.37 (brd, J=8.1 Hz, 1H),5.20-5.08 (m, 3H), 5.03 (s, 2H), 4.72 (m, 1H), 4.20 (m, 1H), 3.92 (brs,2H), 3.29 (brs, 2H), 3.12 (m, 2H), 2.85 (m, 2H), 1.80-1.30 (m, 8H),1.00-0.84 (m, 12H).

EXAMPLE 15

[0929]N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-[(1S,2R)-2-benzoylaminocyclohexyl]carboxamide

[0930] To a solution of the compound prepared in example 13 (398 mg) indimethylformamide (4 ml) were added(1S,2R)-benzamidocyclohexanecarboxylic acid (239 mg),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (185 mg),1-hydroxybenzotriazole (148 mg) and N-methylmorpholine (0.46 ml) at 0°C. and the mixture was stirred for 18 hours at room temperature. To thereaction mixture was added water and was extracted with ethyl acetate.The organic layer was washed with water, a saturated aqueous solution ofsodium bicarbonate and a saturated aqueous solution of sodium chloridesuccessively, dried over anhydrous sodium sulfate and was concentrated.The residue was purified by column chromatography on silica gel(chloroform:methanol=98:2) to give the compound of the present invention(358 mg) having the following physical data.

[0931] TLC: Rf 0.69 (chloroform:methanol=9:1);

[0932] NMR (CDCl₃): δ 7.82 and 7.76 (each d, J=6.0 Hz, totally 2H), 7.54(brd, J=8.2 Hz, 1H), 7.50-7.24 (m, 8H), 6.95 and 6.92 (each d, J=8.4 Hz,totally 1H), 6.80 and 6.77 (each d, J=2.4 Hz, totally 1H), 6.67 and 6.63(each dd, J=8.4, 2.4 Hz, totally 1H), 6.25 and 6.17 (each brd, J=8.1 Hz,totally 1H), 5.01 (s, 2H), 4.69 (m, 1H), 4.31 (m, 1H), 3.92 (m, 2H),3.34 (m, 2H), 3.12 (m, 2H), 2.84 (m, 2H), 2.76 (m, 1H), 2.20-1.20 (m,13H), 0.87, 0.86 and 0.75 (each d, J=6.3 Hz, totally 6H).

EXAMPLE 15(1)-EXAMPLE 15(6)

[0933] By the same procedures as described in example 15 using acarboxylic acid corresponding to (1S,2R)-benzamidecyclohexanecarboxylicacid, the compounds of the present invention having the followingphysical data were obtained.

EXAMPLE 15(1)

[0934]N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

[0935] TLC: Rf 0.61 (chloroform:methanol=9:1);

[0936] NMR (CDCl₃): δ 7.83 and 7.76 (each d, J=7.8 Hz, totally 2H),7.60-7.25 (m, 9H), 6.95 and 6.92 (each d, J=8.4 Hz, totally 1H), 6.80and 6.77 (each d, J=2.4 Hz, totally 1H), 6.67 and 6.63 (each dd, J=8.4,2.4 Hz, totally 1H), 6.30 and 6.20 (each brd, J=8.4 Hz, totally 1H),5.02 (s, 2H), 4.72 (m, 1H), 4.29 (m, 1H), 3.94 (s, 2H), 3.33 (m, 2H),3.15 (m, 2H), 2.90-2.70 (m, 3H), 2.20-1.20 (m, 13H), 0.87, 0.86 and 0.75(each d, J=6.3 Hz, totally 6H)

EXAMPLE 15(2)

[0937]N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-cyclohexylcarboxamide

[0938] TLC: Rf 0.41 (n-hexane:ethyl acetate=1:1);

[0939] NMR (CDCl₃): δ 7.44-7.30 (m, 5H), 6.97 (d, J=8.4 Hz, 1H), 6.80(d, J=2.4 Hz, 1H), 6.66 (dd, J=8.4, 2.4 Hz, 1H) 5.95 (brd, J=8.4 Hz,1H), 5.04 (s, 2H), 4.73 (m, 1H), 3.93 (s, 2H), 3.37 (d, J=16.8 Hz, 1H),3.33 (d, J=16.8 Hz, 1H), 3.16 (t, J=5.4 Hz, 2H), 2.86 (t, J=5.4 Hz, 2H),2.10 (m, 1H), 1.90-1.18 (m, 15H), 0.88 (d, J=6.3 Hz, 6H).

EXAMPLE 15(3)

[0940]N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]benzamide

[0941] TLC: Rf 0.51 (n-hexane:ethyl acetate=1:1);

[0942] NMR (CDCl₃): δ 7.81 (d, J=7.8 Hz, 2H), 7.56-7.30 (m, 8H), 6.97(d, J=8.4 Hz, 1H), 6.80 (m, 3H), 6.66 (dd, J=8.4, 2.4 Hz, 1H), 5.03 (s,2H), 5.00 (m, 1H), 3.93 (s, 2H), 3.43 (d, J=17.4 Hz, 1H), 3.35 (d,J=17.4 Hz, 1H), 3.18 (t, J=5.4 Hz, 2H), 2.86 (t, J=5.4 Hz, 2H),1.90-1.40 (m, 5H), 0.95 (d, J=6.0 Hz, 3H), 0.92 (d, J=6.0 Hz, 3H).

EXAMPLE 15(4)

[0943]N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-3-cyclopentylpropanamide

[0944] TLC: Rf 0.39 (n-hexane:ethyl acetate=1:1);

[0945] NMR (CDCl₃): δ 7.48-7.26 (m, 5H), 6.97 (d, J=8.4 Hz, 1H), 6.80(d, J=2.7 Hz, 1H), 6.68 (dd, J=8.4, 2.7 Hz, 1H), 5.96 (brd, J=7.8 Hz,1H), 5.04 (s, 2H), 4.75 (m, 1H), 3.93 (s, 2H), 3.39 (d, J=16.8 Hz, 1H),3.32 (d, J=16.8 Hz, 1H), 3.17 (t, J=5.4 Hz, 2H), 2.86 (t, J=5.4 Hz, 2H),2.21 (t, J=7.5 Hz, 2H), 1.84-0.93 (m, 16H), 0.89 (d, J=6.3 Hz, 6H).

EXAMPLE 15(5)

[0946]N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-(2-benzyloxyphenyl)carboxamide

[0947] TLC: Rf 0.30 (n-hexane:ethyl acetate=1:1);

[0948] NMR (CDCl₃): δ 8.21 (brd, J=7.2 Hz, 1H), 8.18 (dd, J=7.5, 1.5 Hz,1H), 7.53-7.23 (m, 11H), 7.10 (m, 2H), 6.96 (d, J=7.8 Hz, 1H), 6.78 (d,J=3.0 Hz, 1H), 6.64 (dd, J=7.8, 3.0 Hz, 1H), 5.18 (d, J=10.2 Hz, 1H),5.12 (d, J=10.2 Hz, 1H), 5.01 (s, 2H), 4.70 (m, 1H), 3.99 (brs, 2H),3.40 (m, 2H), 3.20 (m, 2H), 2.86 (m, 2H), 1.80-1.00 (m, 5H), 0.75 (d,J=6.0 Hz, 3H), 0.66 (d, J=6.0 Hz, 3H).

EXAMPLE 15(6)

[0949]N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]cinnamide

[0950] TLC: Rf 0.26 (n-hexane:ethyl acetate=1:1);

[0951] NMR (CDCl₃): δ 7.63 (d, J=15.6 Hz, 1H), 7.55-7.30 (m, 10H), 7.00(d, J=8.1 Hz, 1H), 6.81 (d, J=2.7 Hz, 1H), 6.70 (dd, J=8.1, 2.7 Hz, 1H),6.43 (d, J=15.6 Hz, 1H), 6.34 (brd, J=7.5 Hz, 1H), 5.03 (s, 2H), 4.92(m, 1H), 3.97 (brs, 2H), 3.43 (d, J=17.4 Hz, 1H), 3.34 (d, J=17.4 Hz,1H), 3.19 (m, 2H), 2.85 (m, 2H), 1.84-1.40 (m, 5H), 1.00-0.93 (m, 6H)

EXAMPLE 16

[0952]1-(7-hydroxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-(t-butoxycarbonylamino)-5-methyl-2-hexanone

[0953] To a solution of the compound prepared in Example 12 (1.41 g) inethanol(26 ml) was added 10% palladium-carbon (140 mg) and the mixturewas stirred for 6 hours under atmosphere of hydrogen. The reactionmixture was filtered and the filtrate was concentrated. The residue waspurified by column chromatography on silica gel(chloroform:methanol=97:3) to give the compound of the present invention(275 mg) having the following physical data.

[0954] TLC: Rf 0.38 (chloroform:methanol=9:1);

[0955] NMR (CDCl₃): δ 6.89 (d, J=8.1 Hz, 1H), 6.63 (d, J=2.7 Hz, 1H),6.53 (dd, J=8.1, 2.7 Hz, 1H), 5.00 (brd, J=7.4 Hz, 1H), 4.40 (m, 1H),3.90 (s, 2H), 3.31 (s, 2H), 3.14 (m, 2H), 2.83 (m, 2H), 1.70 (m, 2H),1.60-1.20 (m, 12H), 0.90 (d, J=6.6 Hz, 6H)

EXAMPLE 17

[0956]1-(7-hydroxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-amino-5-methyl-2-hexanonedihydrochloride

[0957] By the same procedure as described in example 2 using thecompound prepared in example 16 in place of the compound prepared inexample 1, the compound of the present invention having the followingphysical data was obtained.

[0958] NMR (DMSO-d₆): δ 9.80 (m, 1H), 8.62 (m, 2H), 7.10 (m, 1H), 6.70(d, J=2.4 Hz, 1H), 6.63 (brd, J=8.4 Hz, 1H), 4.60-4.10 (m, 5H), 3.40 (m,2H), 2.90 (m, 2H), 2.00-1.42 (m, 5H), 1.00-0.80 (m, 6H)

EXAMPLE 18

[0959](2S)-N-[1-(7-hydroxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

[0960] To a solution of the compound prepared in example 17 (120 mg) indimethylformamide (2 ml) were added(2S)-2-benzyloxycarbonylamino-4-methylpentanoic acid (95 mg),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (69 mg),1-hydroxybenzotriazole (55 mg) and N-methylmorpholine (0.084 ml) at 0°C. and the mixture was stirred for 18 hours at room temperature. To thereaction mixture was added water and was extracted with ethyl acetate.The organic layer was washed with water, a saturated aqueous solution ofsodium bicarbonate and a saturated aqueous solution of sodium chloridesuccessively, dried over anhydrous magnesium sulfate and wasconcentrated. The residue was purified by column chromatography onsilica gel (n-hexane:ethyl acetate=1:1) to give the compound (89 mg) ofthe present invention having the following physical data.

[0961] TLC: Rf 0.65 (ethyl acetate);

[0962] NMR (CDCl₃): δ 7.34 (m, 5H), 6.88 (m, 1H), 6.63 (m, 1H), 6.51 (m,1H), 6.58 and 6.40 (each brd, J=7.8 Hz, totally 1H), 5.20-5.08 (m, 3H),4.72 (m, 1H), 4.20 (m, 1H), 3.86 (s, 2H), 3.28 (m, 2H), 3.11 (m, 2H),2.82 (m, 2H), 1.90-1.20 (m, 8H), 1.00-0.84 (m, 12H).

EXAMPLE 18(1)

[0963]N-[1-(7-hydroxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

[0964] By the same procedure as described in example 18 using(−)-2-benzamidocyclohexanecarboxylic acid((1R,2S)-2-benzamidecyclohexanecarboxylic acid) in place of(2S)-2-benzyloxycarbonylamino-4-methylpentanoic acid, the compound ofthe present invention having the following physical data was obtained.

[0965] TLC: Rf 0.33 (ethyl acetate);

[0966] NMR (CDCl₃): δ 7.88-7.70 (m, 2H), 7.62-7.30 (m, 4H), 6.86 and6.80 (each d, J=8.4 Hz, totally 1H), 6.64 and 6.57 (each d, J=2.7 Hz,totally 1H), 6.51 and 6.47 (each dd, J=8.4, 2.7 Hz, totally 1H), 6.17and 6.09 (each brd, J=8.4 Hz, totally 1H), 4.68 (m, 1H), 4.28 (m, 1H),3.91 and 3.86 (each s, totally 2H), 3.32-3.25 (m, 2H), 3.13 (m, 2H),2.90-2.60 (m, 3H), 2.20-1.20 (m, 13H), 0.88 and 0.75 (each d, J=6.3 Hz,totally 6H).

REFERENCE EXAMPLE 8

[0967] 4-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine

[0968] By the same procedure as described in reference example 2 using2,3,4,5-tetrahydro-1H-1,4-benzodiazepine in place of(1R,2S)-2-aminocyclohexylmethylalcohol, the title compound having thefollowing physical data was obtained.

[0969] TLC: Rf 0.70 (n-hexane:ethyl acetate=1:1);

[0970] NMR (CDCl₃): δ 7.21-7.10 (m, 2H), 7.12 (t, J=6.8 Hz, 1H), 6.79(d, J=6.8 Hz, 1H), 4.43-4.35 (m, 2H), 3.65 (m, 2H), 3.15 (m, 2H), 1.53and 1.41 (each s, totally 9H).

REFERENCE EXAMPLE 9

[0971]1-benzyl-4-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine

[0972] Under atmosphere of argon, to a solution of the compound preparedin reference example 8 (276 mg) in dimethylformamide (3.0 ml) was addedpotassium carbonate (336 mg) and the mixture was stirred for 30 minutesat room temperature, then thereto was added benzyl bromide (0.30 ml) andthe mixture was stirred for another 30 hours. To the reaction mixturewas added water and was extracted with ethyl acetate. The organic layerwas washed with a saturated aqueous solution of sodium bicarbonate and asaturated aqueous solution of sodium chloride successively, dried overanhydrous magnesium sulfate and was concentrated. The residue waspurified by column chromatography on silica gel (n-hexane:ethylacetate=9:1) to give the title compound (366 mg) having the followingphysical data.

[0973] TLC: Rf 0.60 (n-hexane:ethyl acetate=3:1);

[0974] NMR (CDCl₃): δ 7.43-7.19 (m, 8H), 7.00 (d, J=8.7 Hz, 1H), 6.93(t, J=8.7 Hz, 1H), 4.55 (m, 2H), 4.37 (s, 2H), 3.48 (m, 2H), 3.00 (m,2H), 1.42 (s, 9H, Boc).

REFERENCE EXAMPLE 10

[0975] 1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine dihydrochloride

[0976] By the same procedure as described in example 2 using thecompound prepared in reference example 9 in place of the compounddescribed in example 1, the title compound having the following physicaldata was obtained.

[0977] TLC: Rf 0.23 (chloroform:methanol=9:1);

[0978] NMR (DMSO-d₆): δ 9.35 (m, 1H), 7.43-7.20 (m, 7H), 7.07 (d, J=8.1Hz, 1H), 6.95 (t, J=7.5 Hz, 1H), 4.41 (m, 2H), 4.24 (m, 2H), 3.20-3.02(m, 4H).

EXAMPLE 19

[0979](3S)-3-amino-1-(1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-heptanonetrihydrochloride

[0980] By the same procedure as described in example 1->example 2 usingthe compound prepared in reference example 10 in place of1,3,4,5-tetrahydro-2-benzazepine, the compound of the present inventionhaving the following physical data was obtained.

[0981] TLC: Rf 0.65 (chloroform:methanol=9:1);

[0982] NMR (DMSO-d₆): δ 8.70 (m, 2H), 7.50-7.21 (m, 7H), 7.06 (d, J=8.1Hz, 1H), 6.98 (t, J=7.5 Hz, 1H), 4.80-4.20 (m, 5H), 3.40 (m, 6H),1.90-1.50 (m, 3H), 1.00-0.90 (m, 6H).

EXAMPLE 20

[0983](2S)-N-[(3S)-5-methyl-2-oxo-1-(1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

[0984] By the same procedure as described in example 14 using thecompound prepared in reference example 10 in place of the compoundprepared in reference example 7, the compound of the present inventionhaving the following physical data was obtained.

[0985] TLC: Rf 0.30 (n-hexane:ethyl acetate=2:1);

[0986] NMR (CDCl₃): δ 7.43-6.82 (m, 14H), 6.39 (brd, J=8.4 Hz, 1H),5.20-5.05 (m, 3H), 4.78 (m, 1H), 4.34 (s, 2H), 4.19 (m, 1H), 3.95 (s,2H), 3.35 (s, 2H), 3.00-2.72 (m, 4H), 1.80-1.21 (m, 6H), 1.00-0.82 (m,12H).

EXAMPLE 21-EXAMPLE 21(3)

[0987] By the same procedure as described in example 3 using thecompound prepared in example 19 in place of the compound prepared inexample 2, and a carboxylic acid corresponding to(−)-2-benzamidecyclohexanecarboxylic acid((1R,2S)-2-benzamidecyclohexanecarboxylic acid), the compounds of thepresent invention having the following physical data were obtained.

EXAMPLE 21

[0988]N-[(3S)-1-(1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-1-cyclohexylcarboxamide

[0989] TLC: Rf 0.68 (n-hexane:ethyl acetate=1:1);

[0990] NMR (CDCl₃): δ 7.43-7.18 (m, 6H), 7.15 (d, J=7.5 Hz, 1H), 7.01(d, J=7.8 Hz, 1H), 6.91 (t, J=7.5 Hz, 1H), 5.93 (brd, J=8.4 Hz, 1H),4.79 (m, 1H), 4.34 (s, 2H), 3.97 (s, 2H), 3.43 (d, J=17.2 Hz, 1H), 3.39(d, J=17.2 Hz, 1H), 3.00-2.80 (m, 4H), 2.12 (m, 1H), 1.90-1.20 (m, 13H),0.90 (d, J=6.3 Hz, 6H)

EXAMPLE 21(1)

[0991]N-[(3S)-1-(1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-3-cyclopentylpropanamide

[0992] TLC: Rf 0.72 (n-hexane:ethyl acetate=1:1);

[0993] NMR (CDCl₃): δ 7.42-7.20 (m, 6H), 7.16 (d, J=8.1 Hz, 1H), 7.03(d, J=7.8 Hz, 1H), 6.93 (t, J=8.1 Hz, 1H), 5.99 (brd, J=8.7 Hz, 1H),4.80 (m, 1H), 4.34 (s, 2H), 4.00 (s, 2H), 3.48 (d, J=17.4 Hz, 1H), 3.41(d, J=17.4 Hz, 1H), 3.00-2.80 (m, 4H), 2.21 (t, J=7.5 Hz, 2H), 1.84-0.92(m, 14H), 0.90 (d, J=6.3 Hz, 6H).

EXAMPLE 21(2)

[0994]N-[(3S)-1-(1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

[0995] TLC: Rf 0.33 (n-hexane:ethyl acetate=1:1);

[0996] NMR (CDCl₃): δ 7.80 (m, 2H), 7.75-7.05 (m, 1H), 7.01 (d, J=7.8Hz, 1H), 6.93 (t, J=8.1 Hz, 1H), 6.20 (brd, J=8.0 Hz, 1H), 4.79 (m, 1H),4.35 (s, 2H), 4.31 (m, 1H), 3.99 (s, 2H), 3.40 (s, 2H), 3.00-2.65 (m,5H), 2.20-1.20 (m, 11H), 1.00-0.70 (m, 6H).

EXAMPLE 21(3)

[0997]N-[(3S)-1-(1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-2-benzyloxybenzamide

[0998] TLC: Rf 0.70 (n-hexane:ethyl acetate=1:1);

[0999] NMR (CDCl₃): δ 8.21 (m, 2H), 7.60-7.02 (m, 15H), 6.99 (d, J=8.1Hz, 1H), 6.88 (t, J=7.5 Hz, 1H), 5.17 (d, J=10.5 Hz, 1H) 5.12 (d, J=10.5Hz, 1H), 4.79 (m, 1H), 4.33 (s, 2H), 3.92 (s, 2H), 3.43 (d, J=17.7 Hz,1H), 3.36 (d, J=17.7 Hz, 1H), 2.98-2.73 (m, 4H), 1.40-0.82 (m, 3H), 0.76(d, J=6.0 Hz, 3H), 0.66 (d, J=6.0 Hz, 3H).

REFERENCE EXAMPLE 11

[1000] ethyl2-(4-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-1-yl)acetate

[1001] To a solution of the compound prepared in reference example 8(2.48 g) in dimethylformamide (1 ml) were added a suspension of sodiumhydride (0.6 g) in dimethylformamide (1 ml) and bromoethyl acetate(1.66ml) at 0° C. and the mixture was stirred for 2.5 hours at 80° C. To thereaction mixture was added water and was extracted with ethyl acetate.The organic layer was washed with water and a saturated aqueous solutionof sodium chloride successively, dried over anhydrous magnesium sulfateand was concentrated. The residue was purified by column chromatographyon silica gel (n-hexane:ethyl acetate 9:9:1) to give the compound of thepresent invention (1.38 g) having the following physical data.

[1002] TLC: Rf 0.68 (n-hexane:ethyl acetate=2:1);

[1003] NMR (CDCl₃): δ 7.18 (m, 2H), 6.91 (dd, J=7.2, 0.9 Hz, 1H), 6.79(m, 1H), 4.40 (m, 2H), 4.23 (q, J=6.9 Hz, 2H), 4.01 (s, 2H), 3.64 (m,2H),. 3.20 (m, 2H), 1.41 (s, 9H), 1.30 (t, J=6.9 Hz, 3H).

REFERENCE EXAMPLE 12

[1004] 2-(2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-1-yl)acetic acid ethylester dihydrochloride

[1005] By the same procedure as described in example 2 using thecompound prepared in reference example 11 in place of the compoundprepared in example 1, the title compound having the following physicaldata was obtained.

[1006] TLC: Rf 0.01 (chloroform:methanol=9:1);

[1007] NMR (DMSO-d₆): δ 9.20 (br, 1H), 7.32 (dd, J=7.5, 1.5 Hz, 1H),7.27 (dt, J=1.5, 7.5 Hz, 1H), 6.93 (dt, J=0.6, 7.2 Hz, 1H), 6.81 (d,J=8.4 Hz, 1H), 4.22-4.03 (m, 6H), 3.42-3.18 (m, 4H), 1.21 (m, 3H).

EXAMPLE 22

[1008](2S)-N-[(3S)-1-(1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

[1009] By the same procedure as described in example 14 using thecompound prepared in reference example 12 in place of the compoundprepared in reference example 7, the compound of the present inventionhaving the following physical data was obtained.

[1010] TLC: Rf 0.33 (n-hexane:ethyl acetate=1:1);

[1011] NMR (CDCl₃): δ 7.34 (s, 5H), 7.26 (t, J=7.8 Hz, 1H), 7.07 (d,J=7.8 Hz, 1H), 6.88 (t, J=7.8 Hz, 1H), 6.74 (d, J=7.8 Hz, 1H), 6.42(brd, J=8.4 Hz, 1H), 5.13 (m, 3H), 4.78 (m, 1H), 4.23 (q, J=6.9 Hz, 2H),4.20 (m, 1H), 3.99 (s, 2H), 3.90 (s, 2H), 3.41 (m, 2H), 3.20 (m, 2H),3.00 (m, 2H), 1.80-1.30 (m, 6H), 1.28 (t, J=6.9 Hz, 3H), 1.00-0.84 (m,12H)

EXAMPLE 22(1)-EXAMPLE 22(4)

[1012] By the same procedure as described in reference example11->reference example 12->example 22 using a halogen compoundcorresponding to bromoacetic acid, the compound of the present inventionhaving the following physical data was obtained.

EXAMPLE 22(1)

[1013](2S)-N-[(3S)-5-methyl-1-(1-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

[1014] TLC: Rf 0.24 (n-hexane:ethyl acetate=1:1);

[1015] NMR (CDCl₃): δ 7.40-6.80 (m, 9H), 6.40 (brd, J=8.2 Hz, 1H),5.20-5.08 (m, 3H), 4.75 (m, 1H), 4.20 (m, 1H), 3.86 (s, 2H), 3.37 (s,2H), 2.97 (s, 4H), 2.89 (s, 3H), 1.80-1.21 (m, 6H), 1.00-0.82 (m, 12H).

EXAMPLE 22(2)

[1016](2S)-N-[(3S)-5-methyl-2-oxo-1-(1-(3-phenylpropyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

[1017] TLC: Rf 0.65 (n-hexane:ethyl acetate=1:1);

[1018] NMR (CDCl₃): δ 7.40-7.04 (m, 12H), 6.88 (m, 2H), 6.60 and 6.44(each brd, J=7.8 Hz, totally 1H), 5.20-5.06 (m, 3H), 4.79 (m, 1H), 4.20(m, 1H), 3.85 (s, 2H), 3.36 (s, 2H), 3.18 (t, J=6.9 Hz, 2H), 2.95 (m,4H), 2.70 (t, J=6.9 Hz, 2H), 1.90 (quintet, J=6.9 Hz, 2H), 1.80-1.30 (m,6H), 1.00-0.82 (m, 12H)

EXAMPLE 22(3)

[1019](2S)-N-[(3S)-5-methyl-2-oxo-1-(1-phenethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

[1020] TLC: Rf 0.71 (n-hexane:ethyl acetate=1:1);

[1021] NMR (CDCl₃): δ 7.40-6.80 (m, 14H), 7.08 (d, J=7.5 Hz, 1H), 6.98(d, J=7.5 Hz, 1H), 6.87 (d, J=7.5 Hz, 1H), 6.38 (m, 1H), 5.12 (m, 3H),4.75 (m, 1H), 4.20 (m, 1H), 3.80 (s, 2H), 3.44 (t, J=6.9 Hz, 2H), 3.35(s, 2H), 3.04 (m, 2H), 2.88 (m, 4H), 1.75-1.30 (m, 6H), 1.00-0.82 (m,12H).

EXAMPLE 22(4)

[1022](2S)-N-[(3S)-5-methyl-1-(1-isopropyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

[1023] TLC: Rf 0.53 (n-hexane:ethyl acetate=1:1);

[1024] NMR (CDCl₃): δ 7.34 (s, 5H), 7.20 (t, J=7.5 Hz, 1H), 7.07 (d,J=7.5 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 6.82 (t, J=7.5 Hz, 2H), 6.40(brd, J=8.1 Hz, 1H), 5.20-5.08 (m, 3H), 4.79 (m, 1H), 4.20 (m, 1H), 3.80(m, 3H), 3.40 (s, 2H), 2.98 (m, 2H), 2.88 (m, 2H), 1.76-1.34 (m, 6H),1.22 (d, J=6.6 Hz, 6H), 1.00-0.85 (m, 12H).

EXAMPLE 23

[1025](2S)-N-[5-methyl-1-(1-carboxymethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

[1026] To a solution of the compound prepared in example 22 (550 mg) intetrahydrofuran (3 ml)-methanol (3 ml) was added 1N aqueous solution ofsodium hydroxide (1 ml) and the mixture was stirred for 2 hours at roomtemperature. The reaction mixture was neutralized by adding 1Nhydrochloric acid and was extracted with ethyl acetate. The organiclayer was washed with a saturated aqueous solution of sodium chloride,dried over anhydrous magnesium sulfate and was concentrated. The residuewas washed with a mixture of hexane-ethyl acetate to give the compoundof the present invention (522 mg) having the following physical data.

[1027] TLC: Rf 0.50 (chloroform:methanol=4:1);

[1028] NMR (DMSO-d₆): δ 8.25 and 8.13 (each brd, J=7.5 Hz, totally 1H),7.40 (brd, J=7.8 Hz, 1H), 7.33 (s, 5H), 7.09 (t, J=7.3 Hz, 1H), 7.02 (d,J=7.3 Hz, 1H), 6.75 (t, J=7.3 Hz, 1H), 6.69 (d, J=7.3 Hz, 1H), 5.00 (s,2H), 4.45-4.30 (m, 1H), 4.04 (m, 1H), 3.90 (brs, 2H), 3.69 (brs, 2H),3.40 (m, 2H), 3.10 (m, 2H), 2.80 (m, 2H), 1.70-1.30 (m, 6H), 0.92-0.70(m, 12H)

EXAMPLE 24

[1029](2S)-N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

[1030] By the same procedure as described in example 14 using2,3,4,5-tetrahydro-1H-1,4-benzodiazepine in place of the compoundprepared in reference example 7, the compound of the present inventionhaving the following physical data.

[1031] TLC: Rf 0.43 (chloroform:methanol=9:1);

[1032] NMR (CDCl₃): δ 7.34 (s, 5H), 7.10 (t, J=7.8 Hz, 1H), 7.05 (d,J=7.8 Hz, 1H), 6.83 (t, J=7.8 Hz, 1H)! 6.75 (d, J=7.8 Hz, 1H), 6.42(brd, J=8.4 Hz, 1H), 5.11 (m, 3H), 4.75 (m, 1H), 4.19 (m, 1H), 3.89 (s,2H), 3.43 (s, 2H), 3.16-3.00 (m, 4H), 1.78-1.32 (m, 6H), 1.00-0.82 (m,12H).

REFERENCE EXAMPLE 13

[1033]2-(4-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-1-yl)aceticacid

[1034] By the same procedure as described in example 23 using thecompound prepared in reference example 11 in place of the compoundprepared in example 22, the compound of the present invention having thefollowing physical data.

[1035] TLC: Rf 0.18 (ethyl acetate);

[1036] NMR (DMSO-d₆): δ 7.10 (m, 2H), 6.82 (m, 1H), 6.65 (m, 1H), 4.38(m, 2H), 3.96 (m, 2H), 3.56 (m, 2H), 3.22 (m, 2H), 1.45-1.23 (m, 9H).

REFERENCE EXAMPLE 14

[1037]2-(4-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-1-yl)acetamide

[1038] To a solution of the compound prepared in reference example 13(400 mg) in dimethylformamide (5 ml) were added ammonium carbonate (308mg) and 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (353 mg) and themixture was stirred for 2 hours at 80° C. To the reaction mixture wasadded a saturated aqueous solution of sodium bicarbonate and wasextracted with ethyl acetate. The organic layer was washed with water, asaturated aqueous solution of sodium bicarbonate and a saturated aqueoussolution of sodium chloride successively, dried over anhydrous magnesiumsulfate and was concentrated. The residue was purified by columnchromatography on silica gel (n-hexane:ethyl acetate=1:1) to give thecompound of the present invention (285 mg) having the following physicaldata.

[1039] TLC: Rf 0.32 (ethyl acetate);

[1040] NMR (CDCl₃): δ 7.40-6.85 (m, 4H), 6.62 and 5.43 (each m, totally2H), 4.51 (m, 2H), 3.89 (s, 2H), 1.43 (m, 9H).

REFERENCE EXAMPLE 15

[1041] 2-(2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-1-yl)acetamidedihydrochloride

[1042] By the same procedure as described in example 2 using thecompound prepared in reference example 14 in place of the compoundprepared in example 1, a crude product having the following physicaldata of the title compound was given. The crude product was used in thenext reaction without further purification.

[1043] TLC: Rf 0.01 (chloroform:methanol:acetic acid=9:1:1).

EXAMPLE 25

[1044](2S)-N-[(3S)-1-(1-aminocarbonylmethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

[1045] By the same procedure as described in example 14 using thecompound prepared in reference example 15 in place of the compoundprepared in reference example 7, the compound of the present inventionhaving the following physical data was obtained.

[1046] TLC: Rf 0.33 (chloroform:methanol=9:1);

[1047] NMR (CDCl₃): δ 7.34 (m, 5H), 7.21 (t, J=6.9 Hz, 1H), 7.10 (d,J=6.9 Hz, 1H), 7.04-6.88 (m, 3H), 6.51 (brd, J=7.5 Hz, 1H), 5.68 (brs,1H), 5.20 (brd, J=7.2 Hz, 1H), 5.10 (s, 2H), 4.70 (m, 1H), 4.21 (m, 1H),3.93 (brs, 2H), 3.90 (s, 2H), 3.50 (d, J=13.2 Hz, 1H), 3.40 (d, J=13.2Hz, 1H), 3.20-2.90 (m, 4H), 1.80-1.38 (m, 6H), 1.05-0.87 (m, 12H).

REFERENCE EXAMPLE 16

[1048]4-(t-butoxycarbonyl)-1-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine

[1049] To a solution of the compound prepared in reference example 11(200 mg) in tetrahydrofuran (3 ml) was added a suspension of lithiumaluminum hydride (34 mg) in tetrahydrofuran at 0° C. and the mixture wasstirred for 2 hours at room temperature. To the reaction mixture wasadded ice-water and 15% aqueous solution of sodium hydroxide and themixture was filtered. The filtrate was concentrated and the residue wasdried under reduced pressure to give the title compound having thefollowing physical data as a crude product. The crude product was usedin the next reaction without further purification.

[1050] TLC: Rf 0.22 (n-hexane:ethyl acetate=2:1);

[1051] NMR (CDCl₃): δ 7.20 (m, 2H), 6.92 (m, 2H), 4.42 (brs, 2H),3.80-3.60 (m, 4H), 3.43 (m, 2H), 3.30-3.10 (m, 2H), 1.35 (s, 9H).

REFERENCE EXAMPLE 17

[1052] 1-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepinedihydrochloride

[1053] By the same procedure as described in example 2 using thecompound prepared in reference example 16 in place of the compoundprepared in example 1, a crude product of the title compound wasobtained. The crude product was used in the next reaction withoutfurther purification.

EXAMPLE 26

[1054](2S)-N-[1-(1-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

[1055] By the same procedure as described in example 14 using thecompound prepared in reference example 17 in place of the compoundprepared in reference example 7, and(2S)-N-[1-bromo-5-methyl-2-oxo-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamidein place of(2S)-N-[(3S)-1-bromo-5-methyl-2-oxo-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide,the compound of the present invention having the following physical datawas obtained.

[1056] TLC: Rf 0.48 (ethyl acetate);

[1057] NMR (CDCl₃): δ 7.40-6.82 (m, 9H), 6.77 and 6.44 (each brd, J=7.8Hz, totally 1H), 5.20-5.08 (m, 3H), 4.70 (m, 1H), 4.20 (m, 1H), 3.87 (m,2H), 3.71 (t, J=5.4 Hz, 2H), 3.41 (m, 4H), 3.05 (m, 2H), 2.97 (m, 2H),1.90-1.30 (m, 6H), 1.00-0.82 (m, 12H).

REFERENCE EXAMPLE 18

[1058]4-(t-butoxycarbonyl)-1-cyanomethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine

[1059] To a solution of the compound prepared in reference example 14(101 mg) in methylene chloride (2 ml) were added pyridine (60 μl) andtosyl chloride(138 mg) at 0° C. and the mixture was stirred for 2 hoursat 80° C. To the reaction mixture was added water and was extracted withethyl acetate. The organic layer was washed with water, a saturatedaqueous solution of sodium bicarbonate and a saturated aqueous solutionof sodium chloride successively, and dried over anhydrous magnesiumsulfate. The residue was purified by column chromatography on silica gel(hexane:ethyl acetate=7:3) to give the compound (33 mg) having thefollowing physical data.

[1060] TLC: Rf 0.88 (chloroform:methanol=9:1);

[1061] NMR (CDCl₃): δ 7.40-7. 20 (m, 2H), 7.11 (d, J=8.1 Hz, 1H), 7.04(t, J=8.1 Hz, 1H), 4.42-4.30 (m, 2H), 4.11 (s, 2H), 3.63 (br, 2H), 3.15(m, 2H), 1.42 (s, 9H).

EXAMPLE 27

[1062](2S)-N-[(3S)-1-(1-cyanomethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

[1063] By the same procedure as described in example 2->example 14 usingthe compound prepared in reference example 18 in place of the compoundprepared in example 1, the compound of the present invention having thefollowing physical data was obtained.

[1064] TLC: Rf 0.26 (n-hexane:ethyl acetate=1:1);

[1065] NMR (CDCl₃): δ 7.40-7.25 (m, 6H), 7.13 (d, J=6.6 Hz, 1H), 7.05(d, J=6.6 Hz, 1H), 7.00 (t, J=6.6 Hz, 1H), 6.35 (brd, J=7.5 Hz, 1H),5.10 (m, 3H), 4.75 (m, 1H), 4.19 (m, 1H), 4.08 (s, 2H), 3.87 (s, 2H),3.36 (m, 2H), 3.18-3.00 (m, 4H), 1.80-1.38 (m, 6H), 1.00-0.88 (m, 12H).

REFERENCE EXAMPLE 19-A-REFERENCE EXAMPLE 19-B

[1066] To a solution of 4-chromanone (5.00 g) in chloroform (60 ml) wereadded under cooling with ice conc. sulfic acid (25 ml) and sodium azide(4.42 g) over a period of 30 minutes and the mixture was stirred for 2hours at room temperature. The reaction mixture was poured intoice-water and the mixture was alkalified with potassium carbonate andwas extracted with methylene chloride. The organic layer was washed withwater, a saturated aqueous solution of sodium bicarbonate and asaturated aqueous solution of sodium chloride successively, dried overanhydrous magnesium sulfate and was concentrated. The residue waspurified by column chromatography on silica gel (toluene:ethylacetate=1:1) to give the compound of reference example 19-A (3.1 g) andthe compound of reference example 19-B (100 mg) having the followingphysical data.

REFERENCE EXAMPLE 19-A

[1067] 2,3,4,5-tetrahydro-1,4-benzoxazepin-5-one

[1068] TLC: Rf 0.45 (chloroform:methanol=9:1);

[1069] NMR (CDCl₃): δ 7.60 (m, 1H), 7.10-6.87 (m, 4H), 4.47 (t, J=6.0Hz, 2H), 2.86 (t, J=6.0 Hz, 2H).

REFERENCE EXAMPLE 19-B

[1070] 2,3,4,5-tetrahydro-1,5-benzoxazepin-4-one

[1071] TLC: Rf 0.48 (chloroform:methanol=9:1);

[1072] NMR (CDCl₃): δ 7.97 (dd, J=11.1, 1.5 Hz, 1H), 7.44 (dt, J=1.5,8.1 Hz, 1H), 7.37 (m, 1H), 7.14 (dt, J=1.2, 8.1 Hz, 1H), 7.02 (dd,J=1.2, 8.1 Hz, 1H), 4.40 (t, J=4.8 Hz, 2H), 3.51 (q, J=4.8 Hz, 2H).

REFERENCE EXAMPLE 20-A

[1073] 2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride

[1074] To a solution of the compound prepared in reference example 19-A(3.05 g) in tetrahydrofuran (30 ml) was added a suspension of lithiumaluminum hydride (2.5 g) in tetrahydrofuran (80 ml) and the mixture wasrefluxed for 24 hours. To the reaction mixture were added ice-water and15% aqueous solution of sodium hydroxide and the mixture was filtered.To the filtrate was added water and the mixture was extracted withmethylene chloride. The organic layer was washed with water and asaturated aqueous solution of sodium chloride successively, dried overanhydrous magnesium sulfate and was concentrated. The residue wasdissolved in ethyl acetate (20 ml) and thereto was added 4N hydrochloricacid-ethyl acetate (40 ml) under cooling with ice, and the mixture wasstirred for 30 minutes at room temperature. The reaction mixture wasconcentrated. The residue was washed with diethyl ether-ethyl acetate(7:3) to give the title compound (3.30 g) having the following physicaldata.

[1075] TLC: Rf 0.71 (chloroform:methanol:water=6:4:1);

[1076] NMR (DMSO-d₆): δ 9.72 (m, 2H), 7.47-7.27 (m, 2H), 7.20-7.01 (m,4H). 3.50 (m, 2H).

REFERENCE EXAMPLE 20-B

[1077] 2,3,4,5-tetrahydro-1,5-benzoxazepine

[1078] To a solution of the compound prepared in reference example 19-B(95 mg) in tetrahydrofuran (1 ml) was added a suspension of lithiumaluminum hydride (77 mg) in tetrahydrofuran (1 ml) at 0° C. and themixture was refluxed for 2 hours. To the reaction mixture was addedice-water and 15% aqueous solution of sodium hydroxide and was filtered.The filtrated was extracted with methylene chloride. The organic layerwas washed with water and a saturated aqueous solution of sodiumchloride successively, dried over anhydrous sodium sulfate and wasconcentrated. The residue was purified by column chromatography onsilica gel (toluene:ethyl acetate=1:1) to give the title compound (45mg) having the following physical data.

[1079] TLC: Rf (n-hexane:ethyl acetate=2:1);

[1080] NMR (CDCl₃): δ 6.96 (dd, J=7.8, 1.5 Hz, 1H), 6.87 (dt, J=1.5, 7.8Hz, 1H), 6.78 (dt, J=1.8, 7.8 Hz, 1H), 6.72 (dd, J=7.8, 1.8 Hz, 1H),6.72 (dd, J=7.8, 1.8 Hz, 1H), 4.40 (t, J=4.8 Hz, 2H), 3.51 (q, J=4.8 Hz,2H).

EXAMPLE 28

[1081](2S)-N-[(3S)-1-(2,3,4,5-tetrahydro-1,4-benzoxazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

[1082] By the same procedure as described in example 14 using thecompound prepared in reference example 20-A in place of the compoundprepared in reference example 7, the compound of the present inventionhaving the following physical data.

[1083] TLC: Rf 0.45 (n-hexane:ethyl acetate=1:1);

[1084] NMR (CDCl₃): δ 7.40-6.95 (m, 9H), 6.34 (brd, J=7.5 Hz, 1H), 5.10(brs, 3H), 4.75 (m, 1H), 4.20 (m, 1H), 4.06 (m, 2H), 3.94 (d, J=14.7 Hz,1H), 3.88 (d, J=14.7 Hz, 1H), 3.44 (s, 2H), 3.14 (m, 2H), 1.80-1.30 (m,6H), 1.00-0.84 (m, 12H).

EXAMPLE 29

[1085](2S)-N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1,5-benzoxazepin-5-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

[1086] By the same procedure as described in Example 14, using thecompound prepared in Reference Example 20-B in place of the compoundprepared in reference example 7, the compound of the present inventionwas obtained.

[1087] TLC: Rf 0.53 (n-hexane:ethyl acetate=2:1);

[1088] NMR (CDCl₃): δ 7.34 (s, 5H), 6.98-6.58 (m, 4H), 6.42 (brd, J=6.6Hz, 1H), 5.10 (m, 3H); 4.78 (m, 1H), 4.23-4.05 (m, 5H), 3.38-3.19 (m,2H), 2.18-1.98 (m, 2H), 1.74-1.40 (m, 6H), 1.00-0.84 (m, 12H).

EXAMPLE 30

[1089]N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1,4-benzoxazepin-4-yl)-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

[1090] By the same procedure as described in example 1->example2->example 3 using the compound prepared in reference example 20-A inplace of 1,3,4,5-tetrahydro-2-benzazepine, the compound of the presentinvention having the following physical data was obtained.

[1091] TLC: Rf 0.30 (n-hexane:ethyl acetate=1:1);

[1092] NMR (CDCl₃): δ 7.77 (dd, J=8.0, 1.8 Hz, 2H), 7.50-7.38 (m, 3H),7.30-6.95 (m, 5H), 6.15 (brd, J=8.0 Hz, 1H), 4.81-4.70 (m, 1H),4.40-4.22 (m, 1H), 4.10-4.00 (m, 2H), 3.91 (d, J=14.8 Hz, 1H), 3.88 (d,J=14.8 Hz, 1H), 3.45 (s, 2H), 3.20-3.10 (m, 2H), 2.82-2.71 (m, 1H),2.20-1.20 (m, 11H), 0.76 (d, J=6.2 Hz, 3H), 0.74 (d, J=6.2 Hz, 3H)

REFERENCE EXAMPLE 21

[1093]2,3,4,5-tetrahydro-1,4-benzothiazepin-5-one

[1094] By the same procedure as described in reference example 5 using3,4-dihydro-2H-1-benzothiin-4-one in place of 6-hydroxy-1-tetralone, thetitle compound having the following physical data was obtained as acrude product. The crude product was used in the next reaction withoutfurther purification.

[1095] TLC: Rf 0.44 (chloroform:methanol=9:1).

REFERENCE EXAMPLE 22

[1096] 2,3,4,5-tetrahydro-1,4-benzothiazepine hydrochloride

[1097] To a solution of the compound prepared in reference example 21(820 mg) in tetrahydrofuran (10 ml) was added boron hydride (1Mtetrahydrofuran solution, 11.5 ml) and the mixture was stirred for 3hours. To the reaction mixture was added methanol and was concentrated.To the residue was added 6N hydrochloric acid and was refluxed for 3hours. The reaction mixture was concentrated to give the title compoundhaving the following physical data as a crude product.

[1098] TLC: Rf 0.48 (chloroform:methanol:acetic acid=9:1:1);

[1099] NMR (DMSO-d₆): δ 9.61 (m, 1H), 7.58 (m, 2H), 7.37 (m, 2H), 4.39(brs, 2H), 3.42 (m, 2H), 3.05 (m, 2H).

EXAMPLE 31

[1100](2S)-N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1,4-benzothiazepin-4-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

[1101] By the same procedure as described in example 14 using thecompound prepared in reference example 22 in place of the compoundprepared in reference example 7, the compound of the present inventionhaving the following physical data was obtained.

[1102] TLC: Rf 0.18 (n-hexane:ethyl acetate=1:1);

[1103] NMR (CDCl₃): δ 7.55 (m, 1H), 7.35 (s, 5H), 7.15 (m, 3H), 6.38(brd, J=7.8 Hz, 1H), 5.11 (m, 3H), 4.72 (m, 1H), 4.20 (m, 3H), 3.38 (m,4H), 2.78 (m, 2H), 1.80-1.35 (m, 6H), 1.05-0.87 (m, 12H).

EXAMPLE 31(1)

[1104]N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1,4-benzothiazepin-4-yl)-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

[1105] By the same procedure as described in example 1->example2->example 3 using the compound prepared in reference example 22 inplace of 1,3,4,5-tetrahydro-2-benzazepine, the compound of the presentinvention having the following physical data was obtained.

[1106] TLC: Rf 0.54 (n-hexane:ethyl acetate=1:1);

[1107] NMR (CDCl₃): δ 7.76 (m, 2H), 7.60-7.32 (m, 4H), 7.30-7.10 (m,4H), 6.10 (brd, J=8.4 Hz, 1H), 4.75 (m, 1H), 4.30 (m, 1H), 4.21 (s, 2H),3.38 (m, 4H), 2.79 (m, 3H), 2.10-1.21 (m, 11H), 0.80 (d, J=6.2 Hz, 6H).

REFERENCE EXAMPLE 23

[1108] 4-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine

[1109] By the same procedure as described in reference example 2 usingthe compound prepared in reference example 22 in place of(1R,2S)-2-aminocyclohexylmethylalcohol, the title compound having thefollowing physical data was obtained.

[1110] TLC: Rf 0.53 (n-hexane:ethyl acetate=3:1);

[1111] NMR (CDCl₃): δ 7.60-7.12 (m, 4H), 4.58 (m, 2H), 3.92 (m, 2H),2.81 (m, 2H), 1.45 (m, 9H).

REFERENCE EXAMPLE 24

[1112]4-(t-butoxycarbonyl)-2,3,4,5-tetrahydro-1,4-benzothiazepine-1,1-dioxide

[1113] To a solution of the compound prepared in reference example 23(140 mg) in methylene chloride (4 ml) was added 3-chloroperbenzoic acid(400 mg) and the mixture was stirred for 2 hours at room temperature.The reaction mixture was concentrated, and to the residue was addedethyl acetate, and the organic layer was washed with water, a saturatedaqueous solution of sodium bicarbonate and a saturated aqueous solutionof sodium chloride successively, and was dried. The residue was purifiedby column chromatography on silica gel (n-hexane:ethyl acetate=3:1) togive the title compound (190 mg) having the following physical data.

[1114] TLC: Rf 0.27 (n-hexane:ethyl acetate=3:1);

[1115] NMR (CDCl₃): δ 8.09 (m, 1H), 7.61-7.35 (m, 3H), 4.73 (s, 2H),4.10 (m, 2H), 3.35 (m, 2H), 1.38 (s, 9H).

REFERENCE EXAMPLE 25

[1116] 2,3,4,5-tetrahydro-1,4-benzothiazepine-1,1-dioxide hydrochloride

[1117] By the same procedure as described in example 2 using thecompound prepared in reference example 24 in place of the compoundprepared in example 1, the title compound having the following physicaldata was obtained.

[1118] TLC: Rf 0.57 (chloroform:methanol:ethyl acetate=9:1:1);

[1119] NMR (DMSO-d₆): δ 9.79 (m, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.85-7.67(m, 3H), 4.58 (s, 2H), 3.83 (m, 2H), 3.70 (m, 2H).

EXAMPLE 32

[1120](2S)-N-[(3S)-5-methyl-2-oxo-1-(1,1-dioxo-2,3,4,5-tetrahydro-1,4-benzothiazepin-4-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

[1121] By the same procedure as described in example 14 using thecompound prepared in reference example 25 in place of the compoundprepared in reference example 7, the compound of the present inventionhaving the following physical data was obtained.

[1122] TLC: Rf 0.36 (n-hexane:ethyl acetate=1:1);

[1123] NMR (CDCl₃): δ 8.08 (dd, J=7.4, 1.8 Hz, 1H), 7.60-7.42 (m, 2H),7.34 (s, 5H), 7.23 (m, 1H), 6.35 (brd, J=7.8 Hz, 1H), 5.15-5.00 (m, 3H),4.62 (m, 1H), 4.39 (brs, 2H), 4.19 (m, 1H), 3.60 (m, 2H), 3.38 (m, 4H),1.80-1.38 (m, 6H), 1.01-0.84 (m, 12H).

EXAMPLE 32(1)

[1124]N-[(3S)-5-methyl-2-oxo-1-(1,1-dioxo-2,3,4,5-tetrahydro-1,4-benzothiazepin-4-yl)-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

[1125] By the same procedure as described in example 1->example2->example 3 using the compound prepared in reference example 25 inplace of 1,3,4,5-tetrahydro-2-benzazepine, the compound of the presentinvention having the following physical data was obtained.

[1126] TLC: Rf 0.39 (chloroform:methanol=9:1);

[1127] NMR (CDCl₃): δ 8.08 (dd, J=7.2, 2.1 Hz, 1H), 7.75 (m, 2H),7.55-7.40 (m, 5H), 7.24 (m, 1H), 7.11 (brd, J=8.4 Hz, 1H), 6.05 (brd,J=8.1 Hz, 1H), 4.63 (q, J=8.1 Hz, 1H), 4.50-4.30 (m, 3H), 3.60 (m, 2H),3.41-3.22 (m, 4H), 2.80 (q, J=5.1 Hz, 1H), 2.10-1.21 (m, 11H), 0.83-0.74(m, 6H).

REFERENCE EXAMPLE 26

[1128] 1,2,4,5-tetrahydro-3,2-benzothiazepine-3,3-dioxide

[1129] To a solution of 2-phenylethanesulfonamide (3.62 g) inmethanesulfonic acid (20 ml)-acetic acid (5 ml) was added a solution oftrioxane (582 mg) in trifluoroacetic acid (3 ml)and the mixture wasstirred for 3 hours at 35° C. To the reaction mixture was added waterand was extracted with chloroform. The organic layer was washed withwater and a saturated aqueous solution of sodium bicarbonate, dried overanhydrous sodium sulfate and was concentrated. The residue was purifiedby column chromatography on silica gel (chloroform:methanol=100:1) togive the title compound (1.78 g) having the following physical data.

[1130] TLC: Rf 0.55 (chloroform:methanol=100:1);

[1131] NMR (CDCl₃): δ 7.40-7.20 (m, 4H), 4.42-4.20 (br, 3H), 3.20-3.05(br, 4H).

EXAMPLE 33

[1132](2S)-N-[(3S)-5-methyl-2-oxo-1-(3,3-dioxo-1,2,4,5-tetrahydro-3,2-benzothiazepin-2-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide

[1133] By the same procedure as described in example 14 using thecompound prepared in reference example 26 in place of the compoundprepared in reference example 7, the compound of the present inventionhaving the following physical data was obtained.

[1134] TLC: Rf 0.70 (n-hexane:ethyl acetate=1:1);

[1135] NMR (CDCl₃): δ 7.42-7.13 (m, 9H), 6.33 (brd, J=6.9 Hz, 1H), 5.11(s, 2H), 5.10 (m, 1H), 4.82-4.30 (br, 3H), 4.19 (m, 1H), 4.03-3.70 (br,2H), 3.40-3.00 (m, 4H), 1.80-1.30 (m, 6H), 1.05-0.83 (m, 12H).

EXAMPLE 33(1)

[1136]N-[(3S)-5-methyl-2-oxo-1-(3,3-dioxo-1,2,4,5-tetrahydro-3,2-benzothiazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide

[1137] By the same procedure as described in example 1->example2->example 3 using the compound prepraed in reference example 26 inplace of 1,3,4,5-tetrahydro-2-benzazepine, the compound of the presentinvention having the following physical data was obtained.

[1138] TLC: Rf 0.42 (n-hexane:ethyl acetate=1:1);

[1139] NMR (DMSO-d₆): δ 8.12 (d, J=7.2 Hz, 1H), 7.83-7.70 (m, 3H),7.57-7.10 (m, 7H), 4.60-4.12 (m, 4H), 3.90-3.50 (m, 2H), 3.40-3.07 (m,4H), 2.72 (m, 1H), 2.11-1.08 (m, 11H), 0.67 (d, J=6.2 Hz, 3H), 0.53 (d,J=6.2 Hz, 3H).

REFERENCE EXAMPLE 27

[1140] 2-(2,2-dimethoxyethylaminosulfonyl)nitrobenzene

[1141] To a solution of 2,2-dimethoxyethylamine (2.61 g) in methylenechloride (100 ml) were added 2-nitrophenylsulfonylchloride (5.0 g) anddiisopropylethylamine (5 ml) dropwise at −78° C. and the mixture wasstirred for 10 minutes at room temperature. To the reaction mixture wasadded 1N hydrochloric acid and was extracted with chloroform. Theorganic layer was washed with a saturated aqueous solution of sodiumchloride, dried over anhydrous sodium sulfate and was concentrated togive the title compound having the following physical data.

[1142] TLC: Rf 0.56 (chloroform:methanol=9:1);

[1143] NMR (CDCl₃): δ 8.20-8.10 (m, 1H), 7.92-7.88 (m, 1H), 7.82-7.70(m, 2H), 5.65-5.50 (m, 1H), 4.37 (t, J=5.6 Hz, 1H), 3.32 (s, 6H), 3.23and 3.20 (each d, J=5.4 Hz, each 1H).

REFERENCE EXAMPLE 28

[1144] 2H,3H,4H,5H-benzo[f]-1,2,5-thiadiazepin-1,1-dione

[1145] To a mixture of zinc (28.5 g) and acetic acid (100 ml) was addedthe compound prepared in reference example 27 (6.6 g) and the mixturewas stirred for 3 hours at 80° C. The mixture was filtered and thefiltrate was concentrated. The resiue was washed with chloroform to givethe title compound (1.10 g) having the following physical data.

[1146] TLC: Rf 0.60 (chloroform:methanol=9:1).

EXAMPLE 34

[1147](2S)-N-[(3S)-1-(1,1-dioxo-(3H,4H,5H-benzo[f]-1,2,5-thiadiazepin-2-yl))-5-methyl-2-oxo-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide

[1148] By the same procedure as described in example 14 using thecompound prepared in reference example 28 in place of the compoundprepared in reference example 7, the compound of the present inventionhaving the following physical data was obtained.

[1149] TLC: Rf 0.40 (n-hexane:ethyl acetate=2:1);

[1150] NMR (CDCl₃): δ 7.79 (dd, J=7.8, 1.2 Hz, 1H), 7.42-7.29 (m, 6H),6.97 (t, J=7.8 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.40 (brd, J=7.8 Hz,1H), 5.10 (m, 3H), 4.72 (m, !H), 4.35 (br, 1H), 4.20 (m, 1H), 4.15 and3.82 (each d, J=7.8 Hz, each 1H), 3.80-3.35 (m, 4H), 1.80-1.38 (m, 6H)₁0 93 (d, J=6.3 Hz; 12H)

EXAMPLE 35-EXAMPLE 35(3)

[1151] By the same procedure as described in example 1->example2->example 3 using corresponding compounds, the compounds of the presentinvention having the following physical data were obtained.

EXAMPLE 35

[1152]N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-(1R,2S)-2-benzoylaminocyclohexylcarboxamide

[1153] TLC: Rf 0.36 (chloroform:methanol=9:1);

[1154] NMR (CDCl₃): δ 7.84 and 7.76 (each d, totally 2H), 7.58-7.38 (m,3H), 7.23 (m, 1H), 7.15-6.99 (m, 2H), 6.85-6.70 (m, 2H), 6.20-6.10 (m,1H), 4.82-4. 65 (m, 1H), 4.38-4.20 (m, 1H), 3.92-3.80 (m, 2H), 3.51-3.38(m, 2H), 3.18-2.90 (m, 4H), 2.82-2.72 (m, 1H), 2.10-1.20 (m, 11H),0.92-0.70 (m, 6H).

EXAMPLE 35(1)

[1155]N-[5-methyl-2-oxo-1-(1-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-(1R,2S)-2-benzoylaminocyclohexylcarboxamide

[1156] TLC: Rf 0.59 (chloroform:methanol=9:1);

[1157] NMR (CDCl₃): δ 7.86-7.73 (m, 2H), 7.58-7.17 (m, 5H), 7.10-7.01(m, 1H), 6.94-6.80 (m, 2H), 6.21-6.11 (m, 1H), 4.82-4.67 (m, 1H),4.37-4.22 (m, 1H), 3.91-3.77 (m, 2H), 3.40-3.30 (m, 2H), 3.03-2.85 (m,7H), 2.82-2.71 (m, 1H), 2.20-1.23 (m, 11H), 1.05-0.73 (m, 6H).

EXAMPLE 35(2)

[1158]N-[5-methyl-2-oxo-1-(1-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-(1R,2S)-2-(4-fluorobenzoylamino)cyclohexylcarboxamide

[1159] TLC: Rf 0.61 (chloroform:methanol=9:1);

[1160] NMR (CDCl₃): δ 7.90-7.72 (m, 2H), 7.54 and 7.33 (each brd, J=7.8Hz, total 1H), 7.29-7.17 (m, 1H), 7.14-7.02 (m, 3H), 6.96-6.80 (m, 2H),6.17 and 6.12 (each brd, J=7.8 Hz, total 1H), 4.83-4.68 (m, 1H),4.32-4.20 (m, 1H), 3.90-3.79 (m, 2H), 3.43-3.32 (m, 2H), 3.10-2.80 (m,7H), 2.78-2.69 (m, 1H), 2.13-1.20 (m, 11H), 1.08-0.73 (m, 6H)

EXAMPLE 35(3)

[1161]N-[(3S)-1-(1,1-dioxo-(3H,4H,5H-benzo[f]-1,2,5-thiadiazepin-2-yl))-5-methyl-2-oxo-3-hexyl]-(1R,2S)-2-benzoylaminocyclohexylcarboxamide

[1162] By the same procedure as described in example 1->example2->example 3 using the compound prepared in reference example 28 inplace of 1,3,4,5-tetrahydrobenzazepine, the title compound having thefollowing physical data was obtained.

[1163] TLC: Rf 0.52 (ethyl acetate);

[1164] NMR (CDCl₃): δ 7.85-7.73 (m, 3H), 7.58-7.23 (m, 4H) 7.13 (brd,J=7.8 Hz, 1H), 6.97 (t, J=8.0 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), 6.14(brd, J=7.4 Hz, 1H), 4.79 (m, 1H), 4.42-4.23 (m, 2H), 4.15 and 3.92(each d, J=18.0 Hz, each 1H), 3.82-3.38 (m, 4H), 2.83-2.72 (m, 1H),2.20-1.21 (m, 11H), 0.82 (d, J=6.2 Hz, 6H).

FORMULATION EXAMPLE Formulation Example 1

[1165] The following components were admixed in a conventional methodand punched out to give 100 tablets each containing 50 mg of activeingredient. N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2- 5.0 gbenzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2- benzamidecyclohexyl]carboxamidecarboxymethylcellulose calcium(disintegrating agent) 0.2 g magnesiumstearate (lubricant) 0.1 g microcrystalline cellulose 4.7 g

Formulation Example 2

[1166] The following components were admixed in a conventional method.The solution was sterilized in conventional method, placed 5 ml portionsinto ampoules and freeze-dried in conventional method to give 100ampoules each containing 20 mg of the active ingredient.N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2- 2.0 gbenzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2- benzamidecyclohexyl]carboxamidemannitol 20 g distilled water 500 ml

1. A benzene-fused heteroring derivative of formula (I),

wherein R is (i) hydrogen, (ii) C1-8 alkyl, (iii) CycA, (iv) C1-8 alkylsubstituted with a group selected from halogen atom, CycA, nitro, CF₃and cyano,

CycA is mono-, bi- or tri-cyclic C3-15 carboring or mono-, bi- ortri-cyclic 3-15 membered heteroring comprising 1-4 of nitrogen, 1-2 ofoxygen and/or 1 of sulfur; R¹⁶ is (1) C1-8 alkyl, (2) C2-8 alkenyl, (3)C2-8 alkynyl, (4) CycA or (5) C1-8 alkyl, C2-8 alkenyl or C2-8 alkynylsubstituted with a group selected from halogen, nitro, CF₃, cyano, CycA,NR¹⁸R¹⁹ and —NHC(O)-CycA; R¹⁷, R¹⁸ and R¹⁹ each independently are,hydrogen or C1-4 alkyl, AA¹ is (i) a single bond, or

 , wherein R¹ and R² are the same or different to represent (i)hydrogen, (ii) C1-8 alkyl, (iii) CycA or (iv) C1-8 alkyl substitutedwith 1-5 of group selected from the following (1)-(8): (1) —NR² ¹R² ²,(2) —OR² ³, (3) —SR² ⁴, (4) —COR² ⁵, (5) —NR² ⁶CONR² ¹R² ², (6)guanidino, (7) CycA, (8) —NR² ⁶SO₂R² ¹; or R¹ and R² are taken togetherto form C2-8 alkylene, wherein one carbon atom may be replaced byoxygen, sulfur or —NR²⁰— and the alkylene may be substituted with—NR²¹R²² or —OR²³, R²⁰ is hydrogen, C1-4 alkyl, —COO—(C1-4 alkyl),phenyl or C1-4 alkyl substituted with phenyl, R₂₁, R²², R²³, R²⁴ and R²⁶are the same or different to represent hydrogen, C1-4 alkyl, phenyl orC1-4 alkyl substituted with phenyl, R²⁵ is C1-4 alkyl, phenyl, —NR²¹R²²,wherein all symbols are the same meanings as above, —OR²³, wherein R²³is the same meaning as above, or C1-4 alkyl substituted with phenyl, R³is hydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl orR³ is taken together with R¹ to form C2-6 alkylene, wherein one carbonatom may be replaced by oxygen, sulfur or —NR²⁰— and the alkylene may besubstituted with —NR²¹R²² or —OR²³, or when AA¹ is

AA¹ and R may be taken together to form

is a 5-12 membered mono- or bi-cyclic heteroring and the other symbolsare the same meanings as above, AA² is (i) a single bond,

 , wherein R⁴ and R⁵ are the same or different to represent (1)hydrogen, (2) C1-8 alkyl, (3) CycA or (4) C1-8 alkyl substituted with1-5 of group selected from the following (a)-(h): (a) —NR⁴ ¹ R⁴ ², (b)—OR⁴ ³, (c) —SR⁴ ⁴, (d) —COR⁴ ⁵, (e) —NR⁴ ⁶CONR⁴ ¹R⁴ ², (f) guanidino,(g) CycA, (h) —NR⁴ ⁶SO₂R⁴ ¹; or R⁴ and R⁵ are taken together to formC2-8 alkylene wherein one carbon atom may be replaced by oxygen, sulfuror —NR⁴⁰— and the alkylene may be substituted with —NR⁴¹R⁴² or —OR⁴³,R⁴⁰ is hydrogen, C1-4 alkyl, —COO—(C1-4 alkyl), phenyl or C1-4 alkylsubstituted with phenyl, R⁴¹, R⁴², R⁴³, R⁴⁴ and R⁴⁶ are the same ordifferent to represent hydrogen, C1-4 alkyl, phenyl or C1-4 alkylsubstituted with phenyl, R⁴⁵ is C1-4 alkyl, phenyl, —NR⁴¹R⁴², whereinall symbols are the same meaning as above, —OR⁴³, wherein R⁴³ is thesame meaning as above, or C1-4 alkyl substituted with phenyl, R⁶ ishydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl or R⁶is taken together with R⁴ to form C2-6 alkylene, wherein one carbon atommay be replaced by oxygen, sulfur or —NR⁴⁰— and the alkylene may besubstituted with —NR⁴¹R⁴² or —OR⁴³, R⁴⁸ is hydrogen, C1-4 alkyl, phenylor C1-4 alkyl substituted with phenyl or when AA¹ is a single bond, R⁴and R⁴⁸ may be taken together to form C2-6 alkylene, wherein one carbonatom may be replaced by oxygen, sulfur or —NR⁴⁷—, wherein R⁴⁷ ishydrogen or C1-4 alkyl, CycC is a 3-17 membered mono- or bi-cyclicheteroring, CycD is a C3-14 mono- or bi-cyclic carboring or a 3-14membered mono- or bi-cyclic heteroring, or AA² and AA¹ are takentogether to form

wherein CycE is a 4-18 membered mono- or bi-cyclic heteroring, CycF is a5-8 membered monocyclic heteroring, and the other symbols are the samemeanings as above, R⁷ and R⁸ are the same or different to represent (i)hydrogen, (ii) C1-8 alkyl, (iii) CycA or (iv) C1-8 alkyl substitutedwith 1-5 of group selected from the following (1)-(8); (1) —NR⁶¹R⁶², (2)—OR⁶³, (3) —SR⁶⁴, (4) —COR⁶⁵, (5) —NR⁶⁶CONR⁶¹R⁶², (6) guanidino, (7)CycA, (8)—NR⁶⁶SO₂R⁶¹, or R⁷ and R⁸ are taken together to form C2-8alkylene, wherein one carbon atom may be replaced by oxygen, sulfur or—NR⁶⁰— and the alkylene may be substituted with —NR⁶¹R⁶² or —OR⁶³, R⁶⁰is hydrogen, C1-4 alkyl, —COO—(C1-4 alkyl), phenyl or C1-4 alkylsubstituted with phenyl, R⁶¹, R⁶², R⁶³, R⁶⁴ and R⁶⁶ are the same ordifferent to represent hydrogen, C1-4 alkyl, phenyl or C1-4 alkylsubstituted with phenyl, R⁶⁵ is C1-4 alkyl, phenyl, —NR⁶¹R⁶², whereinall symbols are the same meanings as above, —OR⁶³, wherein R⁶³ is thesame meaning as above, or C1-4 alkyl substituted with phenyl, R⁹ ishydrogen, C1-8 alkyl, phenyl or C1-8 alkyl substituted with phenyl or R⁹is taken together with R⁷ to form C2-6 alkylene, wherein one carbon atommay be replaced by oxygen, sulfur or —NR⁶⁰— and the alkylene may besubstituted with —NR⁶¹R⁶² or —OR⁶³, r is an integer of 1-4,

in the ring represented by (i), (ii) and (iii), one or two saturatedcarbon atom may be replaced by (1) oxygen, (2) —S(O)_(s)— or (3) —NR⁸³,wherein s is 0 or an integer of 1-2, R⁸³ is (a) hydrogen, (b) C1-8alkyl, (c) CycA or (d) C1-8 alkyl substituted with 1-5 of group selectedfrom CycA, guanidino, —COR⁶⁸, —NR⁶⁹R⁷⁰, —OR⁶⁹, cyano and —P(O)(OR⁷⁵)₂,R⁶⁸ is C1-4 alkyl, phenyl or C1-4 alkyl substituted with phenyl, R⁶⁹ andR⁷⁰ are the same or different to represent hydrogen, C1-4 alkyl, phenylor C1-4 alkyl substituted with phenyl, R⁷⁵ is hydrogen, C1-8 alkyl,phenyl or C1-4 alkyl substituted with 1-5 of phenyl, cyano or halogen,and the rings of (i), (ii) and (iii) may be fused with C5-8 carboring ora 5-8 membered heteroring containing 1-2 of nitrogen, 1 of oxygen and/or1 of sulfur, q is an integer of 0 or 1 to 5, R¹⁰ is (i) C1-8 alkyl, (ii)C2-8 alkenyl, (iii) C2-8 alkynyl, (iv) halogen, (v) CycA, (vi) —COR⁷¹,(vii) —NR⁷²R⁷³, (viii) —OR⁷⁴, or (ix) C1-8 alkyl, C2-8 alkenyl, C2-8alkynyl substituted with 1-5 of group selected from the following<1>-<7>: <1> CycA, <2> guanidino, <3> —COR⁷¹, <4> —NR⁷²R⁷³, <5> —OR⁷⁴,<6> cyano and <7> —P(O)(OR⁸²)₂, wherein R⁸² is hydrogen, C1-8 alkyl,C1-4 alkyl substituted with 1-5 of phenyl, cyano or halogen, R⁷¹ is (1)C1-8 alkyl, (2) CycA, (3) —NR⁷²R⁷³, (4) —OR⁷⁴ or (5) C1-8 alkylsubstituted with CycA, R⁷² and R⁷³ are the same or different torepresent (1) hydrogen, (2) C1-8 alkyl, (3) CycA or (4) C1-8 alkylsubstituted with 1-5 of group selected from the following (a)-(f): (a)CycA, (b) guanidino, (c) —NR⁷⁷R⁷⁸, wherein R⁷⁷ and R⁷⁸ are the same ordifferent to represent hydrogen, C1-4 alkyl, phenyl or C1-4 alkylsubstituted with phenyl, (d) —OR⁷⁷, wherein R⁷⁷ has the same meaning asabove, (e) —COR⁷⁶, wherein R⁷⁶ is C1-4 alkyl, phenyl, —NR⁷⁷R⁷⁸, whereinall symbols have the same meanings as above, —OR⁷⁷, wherein R⁷⁷ has thesame meaning as above, or C1-4 alkyl substituted with phenyl, and (f)cyano; R⁷⁴ is (1) hydrogen, (2) C1-8 alkyl, (3) CycA, or (4) C1-8 alkylsubstituted with 1-5 of groups selected from the following (a)-(h),wherein one carbon atom may be replaced by oxygen, sulfur atom or—NR⁸⁴—; (a) CycA, (b) guanidino, (c) —SiR⁷⁹R⁸⁰R⁸¹, wherein R⁷⁹, R⁸⁰ andR⁸¹ are the same or different to represent, C1-8 alkyl, phenyl or C1-8alkyl substituted with phenyl, (d) —NR⁷⁷R⁷⁸, wherein all symbols havethe same meanings as above, (e) —OR⁷⁷, wherein R⁷⁷ has the same meaningas above, (f) —COR⁷⁶, wherein R⁷⁶ has the same meaning as above, (g)cyano, (h) —P(O)(OR⁸²)₂, wherein all symbols have the same meanings asabove; with proviso that CycA in R, R¹, R², R⁴, R⁵, R⁷, R⁸, R¹⁰, R¹⁶,R⁷¹, R⁷², R⁷³, R⁷⁴, R⁸³ have the same or different, and CycA, CycB,CycC, CycD, CycE and CycF may be, each independently, substituted with1-5 of R²⁷: R²⁷ is (1) C1-8 alkyl, (2) halogen, (3) —NR¹¹R¹², (4) —OR¹³,(5) C5-10 mono- or bi-cyclic carboring, (6) nitro, (7) CF₃, (8) cyano,(9) 5-10 membered mono- or bi-cyclic heteroring, (10) —SR¹⁴, (11)—COR¹⁵, (12) oxo, (13) —SO₂R¹⁵, (14) —OCF₃ or (15) C1-8 alkylsubstituted with 1-5 of group selected from the following (a)-(m): (a)halogen, (b) —NR¹¹R¹², (c) —OR¹³, (d) C5-10 mono- or bi-cycliccarboring, (e) nitro, (f) CF₃, (g) cyano, (h) 5-10 mono- or bi-cyclicheteroring, (j) —SR¹⁴, (k) —COR¹⁵, (l) —SO₂R¹⁵, (m) —OCF₃, wherein R¹¹and R¹² are the same or different to represent, hydrogen, C1-4 alkyl,—COO—(C1-4 alkyl), phenyl or C1-4 substituted with phenyl, R¹³ and R¹⁴are the same or different to represent, hydrogen, C1-4 alkyl, phenyl orC1-4 alkyl substituted with phenyl, R¹⁵ is C1-4 alkyl, phenyl, —NR¹¹R²,wherein all symbols have the same meanings as above, —OR¹³, wherein R¹³has the same meaning as above, or C1-4 alkyl substituted with phenyl, ora non-toxic salt thereof.
 2. The compound according to claim 1, whereinR is (i) hydrogen, (ii) C1-8 alkyl, (iii) CycA, (iv) C1-8 alkylsubstituted with CycA or nitro,

R¹⁶ is (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) CycA, (5)C1-8 alkyl substituted with CycA or —NHC(O)-CycA, (6) C2-8 alkenylsubstituted with CycA, (7) C2-8 alkynyl substituted with CycA, AA¹ is(i) a single bond,

or taken together with R to represent

wherein J¹ is oxygen, sulfur, —NR²⁹—, wherein R²⁹ is hydrogen, C1-4alkyl, CycA or C1-4 alkyl substituted with CycA, C1-3 alkylene or C2-3alkenylene, J² is a single bond or C1-2 alkylene, Y² is —N═CH—, —CH═N—or C1-2 alkylene, J³ is carbonyl or C1-3 alkylene, Y³ is C1-3 alkylene,oxygen or —NR²⁹—, wherein R²⁹ has the same meaning as above, R²⁸ ishydrogen, C1-4 alkyl, CycA or C1-4 alkyl substituted with CycA, or R² istaken together with R¹ to form C2-4 alkylene, and the other symbols havethe same meanings as defined in claim 1, each ring may be substitutedwith 1-5 of R²⁷, AA² is (i) a single bond,

wherein J⁴, Y⁴, L⁴ are the same or different to represent a single bondor C1-3 alkylene, with proviso that J⁴, Y⁴ and L⁴ do not represent asingle bond at the same time, J⁵ is C1-6 alkylene, Y⁵ is a single bond,C1-3alkylene or —NR⁶⁷—, wherein R⁶⁷ is hydrogen, C1-4 alkyl, phenyl orC1-4 alkyl substituted with phenyl, J⁸ is C1-5 alkylene, wherein onecarbon atom may be replaced by oxygen, Y⁸ is a single bond or C1-4alkylene, L⁸ is —N— or —CH—, J⁶ and Y⁶ are the same or different torepresent a single bond or C1-3 alkylene, with proviso that J⁶ and Y⁶ donot represent a single bond at the same time, J⁷ is C1-6 alkylene,wherein one carbon atom may be replaced by oxygen, sulfur or —NR⁶⁷—,wherein R⁶⁷ is the same meaning as above, J⁹ is C1-3 alkylene, oxygen,sulfur or —NR⁶⁷—, wherein R⁶⁷ is the same meaning as above, and eachring may be substituted with 1-5 of R²⁷, or AA² and AA¹ are takentogether to form

wherein

is a single bond or a double bond, J¹⁰ and Y¹⁰ are the same or differentto represent a single bond or C1-3 alkylene, L¹⁰ is a single bond,C1-3alkylene, —NR⁵⁷—, wherein R⁵⁷ is hydrogen, C1-4 alkyl, phenyl orC1-4 alkyl substituted with phenyl, —N═, oxygen or —S(O)_(p)—, wherein pis 0 or an integer of 1-2, J¹² and Y² are the same or different torepresent a single bond or C1-3 alkylene, L¹² is C1-3 alkylene, —NR⁵⁷—,wherein R⁵⁷ has the same meaning as above, —N═, ═N—, oxygen or—S(O)_(p)—, wherein p has the same meaning as above, and the othersymbols are the same meanings as defined in claim 1, and each ring maybe substituted with 1-5 of R²⁷ and AA² and AA¹ are taken together toform

wherein J¹¹ is carbonyl or C2-4 alkylene and the other symbols are thesame meanings as defined in claim 1, and R²⁷ in CycA is (1) C1-8 alkyl,(2) halogen, (3) —NR¹¹R¹², (4) —OR¹³, (5) phenyl, (6) nitro, (7) CF₃,(8) cyano, (9) tetrazole, (10) —SR¹⁴, (11) —COR¹⁵, (12) oxo, or (13)C1-8 alkyl substituted with 1-5 group selected from the following(a)-(k): (a) halogen, (b) —NR¹¹R¹², (c) —OR¹³, (d) phenyl, (e) nitro,(f) CF₃, (g) cyano, (h) tetrazole, (j) SR¹⁴, or (k) COR¹⁵, wherein allsymbols are the same meanings as above, and R¹⁰ is (i) C1-8 alkyl, (ii)CycA, (iii) —COR⁷¹ or (iv) C1-8 alkyl substituted with CycA, guanidino,—COR⁷¹, —NR⁷²R⁷³ or —OR⁷⁴, wherein all symbols have the same meanings asdefined in claim 1, or a non-toxic salt thereof.
 3. A benzene-fusedheteroring derivative according to claim 2, wherein R is C1-8 alkyl, orC1-8 alkyl substituted with CycA or nitro,

and AA¹ is a single bond, or

and AA² is a single bond,


4. A benzene-fused heteroring derivative, according to claim 3, whereinR¹⁶ is C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, CycA or C1-8 alkyl, C2-8alkenyl or C2-8 alkynyl substituted with CycA, wherein CycA is mono- orbi-cyclic C5-10 carboaryl or partially or completely saturated onethereof, or mono- or bi-cyclic 5-10 membered heteroaryl containing 1-2of nitrogen, 1-2 of oxygen and/or 1 of sulfur or partially or completelysaturated one thereof, R¹ is hydrogen, C1-8 alkyl, phenyl, or C1-8 alkylsubstituted with NH₂, C1-4 alkoxy, SH, SCH₃, phenyl, hydroxyphenyl,COOH, CONH₂, guanidino, imidazole or indole and R² is hydrogen or R¹ andR² are taken together to form C3-6 alkylene, R³ is hydrogen or C1-4alkyl or R³ and R¹ are taken together to form C2-4 alkylene, AA² is asingle bond,

R⁴ is hydrogen, C1-8 alkyl, phenyl, or C1-8 alkyl substituted with NH₂,C1-4 alkoxy, SH, SCH₃, phenyl, hydroxyphenyl, COOH, CONH₂, guanidino,imidazole or indole and R⁵ is hydrogen or R⁴ and R⁵ are taken togetherto form C3-6 alkylene, R⁶ is hydrogen or C1-4 alkyl or R⁶ and R⁴ aretaken together to form C2-4 alkylene, R⁴⁸ is hydrogen or C1-4 alkyl, R⁷is hydrogen, C1-8 alkyl, phenyl, or C1-8 alkyl substituted with NH₂,C1-4 alkoxy, SH, SCH₃, phenyl, hydroxyphenyl, COOH, CONH₂, guanidino,imidazole or indole and R⁸ is hydrogen or R⁷ and R⁸ are taken togetherto form C3-6 alkylene, R⁹ is hydrogen or C1-4 alkyl or R⁹ and R⁷ aretaken together to form C2-4 alkylene, or a non-toxic salt thereof.
 5. Abenzene-fused heteroring derivative, according to claim 1, wherein R¹⁶is C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with a groupselected from halogen, nitro, CF₃′ cyano and NR¹⁸R¹⁹, or a non-toxicsalt thereof.
 6. A benzene-fused heteroring derivative according toclaim 1, wherein R¹⁶ is (1) CycA containing 1-5 of substituent R⁷ or (2)C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl substituted with CycAcontaining 1-5 of substituent R²⁷, wherein at least one of R²⁷ includedin (1) and (2) is selected from (i) C5-10 mono- or bi-cyclic carboring,(ii) 5-10 membered mono- or bi-cyclic heteroring, (iii) —SO₂R¹⁵, (iv)—OCF₃ and (v)C1-8 alkyl substituted with 1-5 of group selected from (a)halogen, (b) —NR¹¹R², (c) —OR¹³, (d) C5-10 mono- or bi-cyclic carboring,(e) nitro, (f) CF₃, (g) cyano, (h) 5-10 membered mono- or bi-cyclicheteroring, (j) —SR¹⁴, (k) —COR¹⁵, (1) —SO₂R¹⁵and (m) —OCF₃, wherein atleast one substituent thereof is C5-10 mono- or bi-cyclic carboring,5-10 membered mono- or bi-cyclic heteroring, —SO₂R¹⁵ and —OCF₃, or anon-toxic salt thereof.
 7. A benzene-fused heteroring derivativeaccording to claim 1, wherein AA¹ is a single bond and R⁴⁸ and R aretaken together to form C2-6 alkylene, wherein one carbon atom may bereplaced by —NR⁴⁷—, wherein R⁴⁷ is the same meaning as defined in claim1, oxygen or sulfur, or a non-toxic salt thereof.
 8. A benzene-fusedheteroring according to claim 1, wherein

in the rings (i), (ii), and (iii), one or two saturated carbon atom maybe replaced by (1) oxygen, (2) —S(O)_(s)— or (3) —NR⁸³—, wherein allsymbols have the same meanings as defined in claim 1, which may be fusedwith C5-8 carboring or 5-8 membered heteroring containing 1-2 ofnitrogen, 1 of oxygen and/or 1 of sulfur.
 9. A benzene-fused heteroringderivative according to claim 1, wherein R¹⁰ is C2-8 alkenyl, C2-8alkynyl or C2-8 alkenyl or C2-8 alkynyl substituted with 1-5 of groupselected from CycA, guanidino, —COR⁷¹, —NR⁷²R⁷³, —OR⁷⁴, cyano and—P(O)(OR⁸²)₂, or a non-toxic salt thereof.
 10. A benzene-fusedheteroring derivative according to claim 1, wherein

or a non-toxic salt thereof.
 11. A benzene-fused heteroring derivativeaccording to claim 1, wherein

or a non-toxic salt thereof.
 12. A benzene-fused heteroring derivativeaccording to claim 1, wherein

or a non-toxic salt thereof.
 13. A benzene-fused heteroring derivativeaccording to claim 1, which is (1)(3S)-3-(t-butoxycarbonylamino)-5-methyl-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-2-hexanone,(2)(3S)-3-amino-5-methyl-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-2-hexanone,(3)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-benzamidecyclohexyl]carboxamide, (4)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-cyclohexylcarboxamide,(5)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1S,2R)-2-benzoylaminocyclohexyl]carboxamide, (6)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide,(7)4-benzyloxy-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide,(8)3-benzyloxy-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide,(9)2-benzyloxy-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide,(10)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]cinnamide,(11)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-3-cyclopentylpropanamide,(12)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-2-(5-phenylimidazolidin-2,4-dion-3-yl)acetamide,(13)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-2-(2-phenyl-1,6-dihydropyrimidin-6-on-1-yl)acetamide,(14)2-benzoylamino-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzamide,(15)(3S)-5-methyl-3-(2-methylpropoxycarbonylamino)-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)hexan-2-one,(16)(2S)-N-[5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[1-phenethylpiperidin-2-yl]carboxamide, (17)(2S)-N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide, (18)(2S)-N-[5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide, (19)(2S)-N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide, (20)(2R)-N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide, (21)1-cyclohexyl-N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]carboxamide,(22)N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-3-cyclopentylpropanamide,(23)N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide, (24)N-[(3R)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1S,2R)-2-benzoylaminocyclohexyl]carboxamide, (25)(2S)-N-[1-(2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)acetyl)cyclohexan-1-yl]-4-methyl-2-benzyloxycarbonylamino pentanamide,(26) (2S)-N-[1-(2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)acetyl)cyclohexan-1-yl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide,(27)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-2-(1,3-diazaspiro[4,5]decan-2,4-dione-3-yl)acetamide,(28)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(t-butoxycarbonylamino)cyclohexyl]carboxamide, (29)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-aminocyclohexyl]carboxamide, (30)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-chlorophenylcarbonylamino)cyclohexyl]carboxamide, (31)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-phenylacetylaminocyclohexyl]carboxamide, (32)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-hydrocinnamoylaminocyclohexyl]carboxamide, (33)N-[5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-acetylaminocyclohexyl]carboxamide, (34)N-[5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(6-aminonicotinoyl)aminocyclohexyl]carboxamide, (35)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-(t-butoxycarbonyl)piperazin-1-ylcarbonylamino)cyclohexyl]carboxamide,(36)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(quinoxalin-2-ylcarbonylamino)cyclohexyl]carboxamide, (37)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-naphthoylaminocyclohexyl)carboxamide, (38)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(1-benzothiophen-2-ylcarbonylamino)cyclohexyl]carboxamide,(39)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-methoxybenzoylamino)cyclohexyl]carboxamide, (40)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-nitrobenzoylamino)cyclohexyl]carboxamide,(41)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-phenylbenzoylamino)cyclohexyl]carboxamide,(42)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-fluorobenzoylamino)cyclohexyl]carboxamide,(43)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(2-pyridylcarbonylamino)cyclohexyl]carboxamide, (44)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-t-butylbenzoylamino)cyclohexyl]carboxamide, (45)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(2-methylthionicotinoylamino)cyclohexyl]carboxamide, (46)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(1-naphthylacetylamino)cyclohexyl]carboxamide, (47)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(2-fluorobenzoylamino)cyclohexyl]carboxamide,(48)N-[(3S)-1-(1,3,4,5-tetrahydro-2H-benzazepin-2-yl)-5-methyl-2-oxo-6-hexyl]-1-[(1R,2S)-2-(6-chloronicotinoylamino)cyclohexyl]carboxamide,(49)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-trifluoromethylbenzoylamino)cyclohexyl]carboxamide, (50)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-cyanobenzoylamino)cyclohexyl]carboxamide,(51)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-methylbenzoylamino)cyclohexyl]carboxamide,(52)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-trifluoromethyloxybenzoylamino)cyclohexyl]carboxamide,(53)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(3-t-butyl-1-methylpyrazol-5-ylcarbonylamino)cyclohexyl]carboxamide, (54)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(N,N-di-n-propyl-4-sulfamoyl)benzoylamino]cyclohexyl]carboxamide,(55)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-mesylaminocyclohexyl]carboxamide,(56)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-phenylsulfonylaminocyclohexyl]carboxamide, (57)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(4-dimethylaminobenzoylamino)cyclohexyl]carboxamide, (58)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-(piperazin-1-ylcarbonylamino)cyclohexyl]carboxamide, (59)N-[(3S)-5-methyl-2-oxo-1-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-hexyl]benzenesulfonamide,(60)1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-(t-butoxycarbonylamino)-5-methyl-2-hexanone,(61)3-amino-1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-hexanone,(62)(2S)-N-[(3S)-1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide, (63)N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-[(1S,2R)-2-benzoylaminocyclohexyl]carboxamide, (64)N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide, (65)N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-cyclohexylcarboxamide,(66)N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]benzamide,(67)N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-3-cyclopentylpropanamide,(68)N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-(2-benzyloxyphenyl)carboxamide,(69)N-[1-(7-benzyloxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]cinnamide,(70)1-(7-hydroxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-(t-butoxycarbonylamino)-5-methyl-2-hexanone,(71)1-(7-hydroxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-3-amino-5-methyl-2-hexanone,(72)(2S)-N-[1-(7-hydroxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide, (73)N-[1-(7-hydroxy-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)-5-methyl-2-oxo-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide,(74)(3S)-3-amino-1-(1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-heptanone,(75)(2S)-N-[(3S)-5-methyl-2-oxo-1-(1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide,(76)N-[(3S)-1-(1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-1-cyclohexylcarboxamide,(77)N-[(3S)-1-(1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-3-cyclopentylpropanamide, (78)N-[(3S)-1-(1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide,(79)N-[(3S)-1-(1-benzyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-2-benzyloxybenzamide, (80)(2S)-N-[(3S)-1-(1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide,(81)(2S)-N-[(3S)-5-methyl-1-(1-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide, (82)(2S)-N-[(3S)-5-methyl-2-oxo-1-(1-(3-phenylpropyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide,(83)(2S)-N-[(3S)-5-methyl-2-oxo-1-(1-phenethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide, (84)(2S)-N-[(3S)-5-methyl-1-(1-isopropyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide, (85)(2S)-N-[5-methyl-1-(1-carboxymethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide,(86)(2S)-N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide,(87)(2S)-N-[(3S)-1-(1-aminocarbonylmethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide,(88)(2S)-N-[1-(1-(2-hydroxyethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide, (89)(2S)-N-[(3S)-1-(1-cyanomethyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide, (90)(2S)-N-[(3S)-1-(2,3,4,5-tetrahydro-1,4-benzoxazepin-4-yl)-5-methyl-2-oxo-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide, (91)N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1,4-benzoxazepin-4-yl)-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide, (92)(2S)-N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1,4-benzothiazepin-4-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide,(93)N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1,4-benzothiazepin-4-yl)-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide,(94) (2S)-N-[(3S)-5-methyl-2-oxo-1-(1,1-dioxo-2,3,4,5-tetrahydro-1,4-benzothiazepin-4-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide, (95)N-[(3S)-5-methyl-2-oxo-1-(1,1-dioxo-2,3,4,5-tetrahydro-1,4-benzothiazepin-4-yl)-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide, (96)(2S)-N-[(3S)-5-methyl-2-oxo-1-(3,3-dioxo-1,2,4,5-tetrahydro-3,2-benzothiazepin-2-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamide, (97)N-[(3S)-5-methyl-2-oxo-1-(3,3-dioxo-1,2,4,5-tetrahydro-3,2-benzothiazepin-2-yl)-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide, (98)(₂S)-N-[(3S)-1-(1,1-dioxo(3H,4H,5H-benzo[f]1,2,5-thiadiazepin-2-yl))-5-methyl-2-oxo-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide,(99)N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-(1R,2S)-2-benzoylaminocyclohexylcarboxamide, (100)N-[5-methyl-2-oxo-1-(1-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-(1R,2S)-2-benzoylaminocyclohexylcarboxamide, (101)N-[5-methyl-2-oxo-1-(1-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-4-yl)-3-hexyl]-(1R,2S)-2-(4-fluorobenzoylamino)cyclohexylcarboxamide, or (102)N-[(3S)-1-(1,1-dioxo(3H,4H,5H-benzo[f]1,2,5-thiadiazepin-2-yl))-5-methyl-2-oxo-3-hexyl]-(1R,2S)-2-benzoylaminocyclohexylcarboxamide,or a non-toxic salt thereof.
 14. A benzene-fused heteroring derivativeaccording to claim 1, which is (1)(3S)-3-(t-butoxycarbonylamino)-5-methyl-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)hexan-2-one,(2)(3S)-3-amino-5-methyl-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)hexan-2-one,(3)N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-1-[(1R,2S)-2-benzoylaminocyclohexyl]carboxamide, (4)(2S)-N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-4-methyl-2-benzyloxycarbonylaminopentanamide, (5)N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-1-cyclohexylcarboxamide,(6)N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-4-benzyloxybenzamide,(7)N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-3-benzyloxybenzamide,(8)N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-2-benzyloxybenzcarboxamide,(9)N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-1-[(1S,2R)-2-benzoylaminocyclohexyl]carboxamide, (10)N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexylI]benzamide,(11)N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]-3-cyclopentylpropanamide,(12)N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]cinnamide,(13)N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)-3-hexyl]benzenesulfonamide,or (14)(2S)-N-[(3S)-5-methyl-2-oxo-1-(2,3,4,5-tetrahydro-1,5-benzoxazepin-5-yl)-3-hexyl]-2-benzyloxycarbonylamino-4-methylpentanamideor a non-toxic salt thereof.
 15. A pharmaceutical composition comprisinga benzene-fused heteroring of formula (I) described in claim 1, or anon-toxic salt thereof, as active ingredient.
 16. A cysteine proteaseinhibitor containing a benzene-fused heteroring of formula (I) describedin claim 1, or a non-toxic salt thereof, as active ingredient.
 17. Theinhibitor according to claim 16, wherein cysteine protease is cathepsinK, cathepsin S, cathepsin L, cathepsin B, cathepsin H, calpain orcaspase-1.
 18. An agent for the prophylaxis and/or treatment ofinflammatory diseases, diseases induced by apoptosis, diseases inducedby disorders of immune responses, autoimmune diseases, diseases inducedby decomposition of proteins which compose organism, shock, circulatorysystem disorders, blood coagulation system disorders, malignant tumors,acquired immune deficiency syndrome (AIDS) and AIDS related complex(ARC), parasitic diseases, nerve denaturization diseases, pulmonarydisorders, bone resorption diseases, endocrinesthenia comprising abenzene-fused heteroring derivative of formula (I) described in claim 1,or a non-toxic salt thereof, as active ingredient.